Aryl- and heteroarylcarbonyl derivatives of benzomorphanes and related scaffolds, medicaments containing such compounds and their use

ABSTRACT

The present invention relates to compounds defined by formula I 
                         
wherein the groups R 1  to R 3 , X, m, n and o are defined as in claim  1 , possessing valuable pharmacological activity. Particularly the compounds are inhibitors of 11β-hydroxysteroid dehydrogenase (HSD) 1 and thus are suitable for treatment and prevention of diseases which can be influenced by inhibition of this enzyme, such as metabolic diseases, in particular diabetes type 2, obesity and dyslipidemia.

The present invention relates to compounds derived from the followingchemical scaffold which is structurally defined by the formula I

wherein the groups R¹ to R³, X, m, n and o are as defined hereinafter,including the tautomers, the stereoisomers, the mixtures thereof and thesalts thereof. The invention further relates to pharmaceuticalcompositions containing a compound of formula I according to theinvention as well as the use of a compound according to the inventionfor preparing a pharmaceutical composition for the treatment ofmetabolic disorders. In addition, the invention relates to processes forpreparing a pharmaceutical composition as well as a compound accordingto the invention.

In the literature, compounds which have an inhibitory effect on theenzyme 11β-hydroxysteroid dehydrogenase (HSD) 1 are proposed for thetreatment of the metabolic syndrome, in particular diabetes type 2,obesity and dyslipidemia.

In the scientific publications Acta Poloniae Pharmaceutica 1982, 39, p.61-64 and Acta Poloniae Pharmaceutica 1986, 43, p. 403-405 the synthesesof the following benzomorphanes, that may have various pharmacologicalactivities, particularly analgetic activity, are described:

The scientific publication Chem. Ber. 1976, 109, p. 2657-2669 reportsthe following microbiological transformations of a benzomorphane:

The scientific publication Heterocycles 1980, 14, p. 1983-1988 describesa method for the synthesis of the following heteromorphanes:

In the scientific publications Tetrahedron 2007, 63, p. 7523-7531 andSynthesis 2007, p. 161-163 the formal syntheses of (+)- and(−)-aphanorphine are reported that leads via the pure enantiomers of thefollowing benzomorphane as intermediates:

The patent DE 23 38 369 describes a microbiological hydroxylation methodfor the preparation of benzomorphanes of the general formula

wherein R¹, R², Q′, and Z′ are as described therein.

In the WO 03/097608 opioid and opioid-like compounds of the generalformula R-A-X wherein R, A and X are as defined therein, are describedfor the treatment and prevention of septic shock and other disorders.Inter alia A denotes benzomorphanes of the general formula

In the U.S. Pat. No. 4,108,857 derivatives of benzomorphanes of thegeneral formula

are described as compounds having anticonvulsant, central nervous systemdepressant and diuretic activity.

In the DE 23 54 002 derivatives of benzomorphanes of the general formula

wherein R¹, R², R³, and R⁵ are as defined therein and R⁴ is2-methoxymethylfuran-3-yl or 3-methoxymethylfuran-2-yl, are described asintermediates for the preparation of the correspondingN-furanylmethyl-benzomorphanes.

In the DE 2 229 695 derivatives of benzomorphanes of the general formula

wherein R, R¹, R², R³, and Y are as defined therein, are described asintermediates for the preparation of benzomorphanes that may be usefulas analgesics and antitussives.

In the DE 2 108 954 derivatives of benzomorphanes of the general formula

wherein R′, R¹, and Z are as defined therein, are principally describedas possible intermediates for the preparation of benzomorphanes that mayhave valuable therapeutic properties.

In the DE 2 105 743 derivatives of benzomorphanes of the general formula

wherein R¹, R², R⁴, and Z are as defined therein, are described asprinciple intermediates for the preparation of benzomorphanes that mayhave analgetic activity.

In the U.S. Pat. No. 3,703,529 tricyclic nitrogen-containing compoundsof the general formula

wherein R, R¹, R², X, and Y are as defined therein, that may be usefulas anti-inflammatory and analgesic agents, are described.

The inventors are not aware that N-aryl- or heteroarylcarbonylderivatives of benzomorphanes have been described as inhibitors of11β-hydroxysteroid dehydrogenase (HSD) 1.

AIM OF THE INVENTION

The aim of the present invention is to find new benzomorphanes orrelated compounds, particularly those which are active with regard tothe enzyme 11β-hydroxysteroid dehydrogenase (HSD) 1. A further aim ofthe present invention is to discover benzomorphanes or related compoundswhich have an inhibitory effect on the enzyme 11β-hydroxysteroiddehydrogenase (HSD) 1 in vitro and/or in vivo and possess suitablepharmacological and pharmacokinetic properties to use them asmedicaments.

A further aim of the present invention is to provide new pharmaceuticalcompositions which are suitable for the prevention and/or treatment ofmetabolic disorders, particularly diabetes and dyslipidemia.

Other aims of the present invention will become apparent to the skilledman directly from the foregoing and following remarks.

OBJECT OF THE INVENTION

In a first aspect the present invention relates in its broadestembodiment to compounds derived from the following chemical scaffoldswhich are structurally defined by the formula I

wherein

-   R¹ denotes aryl or heteroaryl,    -   while by aryl is meant phenyl or naphthyl and    -   by heteroaryl is meant pyrrolyl, furanyl, thienyl, pyridyl,        indolyl, benzofuranyl, benzothiophenyl, quinolinyl,        isoquinolinyl, or    -   pyrrolyl, furanyl, thienyl, pyridyl in which 1 or 2 CH are        replaced by N, or    -   indolyl, benzofuranyl, benzothiophenyl, quinolinyl, or        isoquinolinyl, wherein 1 to 3 CH are replaced by N, or    -   1,2-dihydro-2-oxo-pyridinyl, 1,4-dihydro-4-oxo-pyridinyl,        2,3-dihydro-3-oxo-pyridazinyl,        1,2,3,6-tetrahydro-3,6-dioxo-pyridazinyl,        1,2-dihydro-2-oxo-pyrimidinyl, 3,4-dihydro-4-oxo-pyrimidinyl,        1,2,3,4-tetrahydro-2,4-dioxo-pyrimidinyl,        1,2-dihydro-2-oxo-pyrazinyl,        1,2,3,4-tetrahydro-2,3-dioxo-pyrazinyl, indanyl, 1-oxo-indanyl,        2,3-dihydro-indolyl, 2,3-dihydro-1H-isoindolyl,        2,3-dihydro-2-oxo-indolyl, 2,3-dihydro-1-oxo-isoindolyl,        2,3-dihydrobenzo-furanyl, 2,3-dihydro-2-oxo-1H-benzimidazolyl,        2,3-dihydro-2-oxo -benzoxazolyl, benzo[1,3]dioxolyl,        2-oxo-benzo[1,3]dioxolyl, 1,2,3,4-tetrahydro-naphthyl,        1,2,3,4-tetrahydro-quinolinyl,        1,2,3,4-tetrahydro-2-oxo-quinolinyl,        1,2-dihydro-2-oxo-quinolinyl, 1,4-dihydro-4-oxo-quinolinyl,        1,2,3,4-tetrahydro-isoquinolinyl,        1,2,3,4-tetrahydro-1-oxo-isoquinolinyl,        1,2-dihydro-1-oxo-isoquinolinyl, 1,4-dihydro-4-oxo -cinnolinyl,        1,2-dihydro-2-oxo-quinazolinyl, 1,4-dihydro-4-oxo-quina-zolinyl,        1,2,3,4-tetrahydro-2,4-dioxo-quinazolinyl,        1,2-dihydro-2-oxoquinoxalinyl,        1,2,3,4-tetrahydro-3-oxo-quinoxalinyl,        1,2,3,4-tetrahydro-2,3-dioxo-quinoxalinyl, 1,2-dihydro-1-oxo        -phthalazinyl, 1,2,3,4-tetrahydro-1,4-dioxo-phthalazinyl,        chromanyl, coumarinyl, 2,3-dihydro-benzo[1,4]dioxin-yl, or        3,4-dihydro-3-oxo-2H-benzo[1,4]oxazinyl,    -   wherein the above-mentioned aryl or heteroaryl rings are        optionally substituted with one R⁴, one to four identical or        different R⁵, and one R⁶, and all heteroaryl rings are attached        to the carbonyl group via a carbon atom,

R² and R³ together with the double bond to which they are attacheddenote

-   -   a benzo ring optionally substituted with R⁷, R⁸ and R⁹,    -   a pyrido ring optionally substituted with R⁷, R⁸ and R⁹,    -   a pyrrolo, furo, thieno, pyridazino, pyrimido or pyrazino ring        optionally substituted with two substituents selected from R⁷,        R⁸ and R⁹,    -   a pyrazolo, imidazo, oxazolo, thiazolo, isoxazolo, or        isothiazolo ring optionally substituted with R⁷, or    -   a 1,2,3-triazolo ring optionally substituted with C₁₋₄-alkyl or        with phenyl that is optionally additionally substituted with one        to three R¹⁰,

R⁴ denotes fluorine, chlorine, bromine, iodine,

-   -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, hydroxy, C₁₋₄-alkyloxy,    -   nitro, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino,        pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl, piperidin-1-yl,        2-oxo-piperidin-1-yl, morpholin-4-yl, 3-oxo-morpholin-4-yl,        piperazin-1-yl, 2-oxo-piperazin-1-yl, 3-oxo-piperazin-1-yl,        4-(C₁₋₃-alkyl)-piperazin-1-yl,        4-(C₁₋₄-alkylcarbonyl)-piperazin-1-yl,        4-(C₃₋₆-cycloalkylcarbonyl)-piperazin-1-yl,        4-(C₁₋₄-alkyloxycarbonyl)-piperazin-1-yl,        4-(C₁₋₄-alkylsulfonyl)-piperazin-1-yl,        2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,        3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,    -   C₁₋₃-alkyl-carbonylamino, (het)aryl-carbonylamino,        (het)aryl-C₁₋₃-alkyl-carbonylamino, C₁₋₃-alkyloxy-carbonylamino,        aminocarbonylamino, C₁₋₃-alkyl-aminocarbonylamino, di        -(C₁₋₃-alkyl)aminocarbonylamino, pyrrolidin-1-yl-carbonylamino,        piperidin-1-yl-carbonylamino, morpholin-4-yl-carbonylamino,        piperazin-1-yl-carbonylamino, 4-(C₁₋₃-alkyl)        -piperazin-1-yl-carbonylamino, C₁₋₃-alkyl-sulfonylamino,        aminosulfonylamino, C₁₋₃-alkyl -amino-sulfonylamino,        di-(C₁₋₃-alkyl)amino-sulfonylamino,        pyrrolidin-1-yl-sulfonylamino, piperidin-1-yl-sulfonylamino,        morpholin-4-yl-sulfonylamino, piperazin-1-yl-sulfonyl -amino,        4-(C₁₋₃-alkyl)-piperazin-1-yl-sulfonylamino,        (C₁₋₃-alkyloxy-carbonylamino)carbonylamino,        (het)arylsulfonylamino, (het)aryl-C₁₋₃-alkyl-sulfonylamino,    -   N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-carbonylamino,        N—(C₁₋₃-alkyl)-(het)arylcarbonylamino,        N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkyl-carbonylamino,        N—(C₁₋₃-alkyl)-C₁₋₃-alkyloxy-carbonylamino, N        -(aminocarbonyl)-C₁₋₃-alkylamino,        N—(C₁₋₃-alkyl-aminocarbonyl)-C₁₋₃-alkylamino, N-[di        -(C₁₋₃-alkyl)aminocarbonyl]-C₁₋₃-alkylamino,        N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-sulfonylamino,        N—(C₁₋₃-alkyl)-(het)arylsulfonylamino,        N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkyl-sulfonylamino,    -   oxo-imidazolidin-1-yl, 2,4-dioxo-imidazolidin-1-yl,        2,5-dioxo-imidazolidin-1-yl, 2-oxo -hexahydropyrimidin-1-yl,        wherein the nitrogen atom in position 3 of the aforementioned        groups is optionally substituted with methyl or ethyl,    -   cyano, carboxy, C₁₋₃-alkyloxy-carbonyl, aminocarbonyl,        C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,        pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl,        morpholin-4-yl -carbonyl, piperazin-1-yl-carbonyl,        4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl, (het)arylamino        -carbonyl, N—(C₁₋₃-alkyl)-(het)arylaminocarbonyl,        (het)aryl-C₁₋₃-alkylaminocarbonyl,        N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkylaminocarbonyl,    -   C₁₋₃-alkyl-carbonyl, (het)aryl-carbonyl,    -   carboxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyl,        cyano-C₁₋₃-alkyl, aminocarbonyl -C₁₋₃-alkyl,        C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyl,        di-(C₁₋₃-alkyl)-aminocarbonyl -C₁₋₃-alkyl,        pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl,        piperidin-1-yl-carbonyl-C₁₋₃-alkyl, morpholin-4-yl        -carbonyl-C₁₋₃-alkyl, piperazin-1-yl-carbonyl-C₁₋₃-alkyl,        4-(C₁₋₃-alkyl)-piperazin-1-yl -carbonyl-C₁₋₃-alkyl,    -   carboxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyloxy,        cyano-C₁₋₃-alkyloxy, amino -carbonyl-C₁₋₃-alkyloxy,        C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyloxy, di-(C₁₋₃-alkyl)-amino        -carbonyl-C₁₋₃-alkyloxy,        pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl-oxy,        piperidin-1-yl-carbonyl-C₁ ₋₃-alkyloxy,        morpholin-4-yl-carbonyl-C₁₋₃-alkyl-oxy,        piperazin-1-yl-carbonyl-C₁₋₃-alkyloxy,        4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl-C₁₋₃-alkyloxy,    -   hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-C₁₋₃-alkyl, amino-C₁₋₃-alkyl,        C₁₋₃-alkylamino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,        pyrrolidin-1-yl-C₁₋₃-alkyl, 2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyl,        piperidin-1-yl-C₁₋₃-alkyl, 2-oxo-piperidin-1-yl-C₁₋₃-alkyl,        morpholin-4-yl-C₁₋₃-alkyl, 3-oxo -morpholin-4-yl-C₁₋₃-alkyl,        piperazin-1-yl-C₁₋₃-alkyl, 2-oxo -piperazin-1-yl-C₁₋₃-alkyl,        3-oxo-piperazin-1-yl-C₁₋₃-alkyl, 4-(C₁₋₃-alkyl)        -piperazin-1-yl-C₁₋₃-alkyl,        2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyl,        3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyl,    -   C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl,        arylcarbonylamino-C₁₋₃-alkyl,    -   hydroxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-C₁₋₃-alkyloxy,        C₁₋₃-alkylsulfanyl-C₁₋₃-alkyloxy,        C₁₋₃-alkylsulfinyl-C₁₋₃-alkyloxy,        C₁₋₃-alkylsulfonyl-C₁₋₃-alkyloxy, amino-C₁₋₃-alkyloxy,        C₁₋₃-alkylamino-C₁₋₃-alkyloxy,        di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyloxy,        pyrrolidin-1-yl-C₁₋₃-alkyloxy,        2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyloxy,        piperidin-1-yl-C₁₋₃-alkyloxy,        2-oxo-piperidin-1-yl-C₁₋₃-alkyloxy,        morpholin-4-yl-C₁₋₃-alkyloxy,        3-oxo-morpholin-4-yl-C₁₋₃-alkyloxy,        piperazin-1-yl-C₁₋₃-alkyloxy,        2-oxo-piperazin-1-yl-C₁₋₃-alkyloxy,        3-oxo-piperazin-1-yl-C₁₋₃-alkyloxy,        4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyloxy,        2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyloxy,        3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyloxy,    -   C₁₋₃-alkylsulfanyl, C₁₋₃-alkysulfinyl, C₁₋₃-alkylsulfonyl,        C₁₋₃-alkylsulfonyloxy, (het)aryl -sulfonyl,        (het)arylsulfonyloxy, trifluoromethylsulfanyl,        trifluoromethylsulfinyl, trifluoro-methylsulfonyl,    -   aminosulfonyl, C₁₋₃-alkyl-aminosulfonyl,        di-(C₁₋₃-alkyl)-aminosulfonyl, pyrrolidin-1-yl -sulfonyl,        piperidin-1-yl-sulfonyl, morpholin-4-yl-sulfonyl,        piperazin-1-yl-sulfonyl, 4-(C₁₋₃-alkyl)-piperazin-1-yl-sulfonyl,    -   difluoromethyl, trifluoromethyl, difluoromethoxy,        trifluoromethoxy,    -   2,2,2-trifluoro-1-hydroxyethyl,        2,2,2-trifluoro-1-hydroxy-1-methylethyl,        2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl,    -   C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyloxy,    -   C₃₋₆-cycloalkyl-C₁₋₃-alkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyloxy,    -   (het)aryl, (het)aryloxy, (het)aryl-C₁₋₃-alkyl,        (het)aryl-C₁₋₃-alkyloxy, (het)aryloxy-C₁₋₃-alkyl, or    -   tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,        tetrahydropyran-4-yl-oxy, tetrahydro-furanyl -C₁₋₃-alkyloxy,        tetrahydropyranyl-C₁₋₃-alkyloxy,    -   wherein the above-mentioned azetidin-1-yl, pyrrolidin-1-yl and        piperidin-1-yl moieties are optionally substituted with one or        two groups selected from methyl, ethyl, methoxymethyl, hydroxy        or methoxy, and,    -   wherein the above-mentioned piperazin-1-yl and morpholin-4-yl        moieties are optionally substituted with one or two groups        selected from methyl, ethyl or methoxymethyl, and    -   wherein the above-mentioned (het)aryl is phenyl, naphthyl,        pyrrolyl, furanyl, thienyl, tetrazolyl, pyridyl, indolyl,        benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, or    -   pyrrolyl, furanyl, thienyl, pyridyl in which 1 or 2 CH are        replaced by N, or    -   indolyl, benzofuranyl, benzothiophenyl, quinolinyl,        isoquinolinyl in which 1 to 3 CH are replaced by N, or    -   1,2-dihydro-2-oxo-pyridinyl, 1,4-dihydro-4-oxo-pyridinyl,        2,3-dihydro-3-oxo-pyridazinyl,        1,2,3,6-tetrahydro-3,6-dioxo-pyridazinyl,        1,2-dihydro-2-oxo-pyrimidinyl, 3,4-dihydro-4-oxo-pyrimidinyl,        1,2,3,4-tetrahydro-2,4-dioxo-pyrimidinyl,        1,2-dihydro-2-oxo-pyrazinyl,        1,2,3,4-tetrahydro-2,3-dioxo-pyrazinyl,        2,3-dihydro-2-oxo-indolyl, 2,3-dihydrobenzo-furanyl,        2,3-dihydro-2-oxo-1H-benzimidazolyl,        2,3-dihydro-2-oxo-benzoxazolyl, 1,2-dihydro-2-oxo-quinolinyl,        1,4-dihydro-4-oxo-quinolinyl, 1,2-dihydro-1-oxo-isoquinolinyl,        1,4-dihydro-4-oxo-cinnolinyl, 1,2-dihydro-2-oxo-quinazolinyl,        1,4-dihydro-4-oxo-quinazolinyl,        1,2,3,4-tetrahydro-2,4-dioxo-quinazolinyl,        1,2-dihydro-2-oxoquinoxalinyl,        1,2,3,4-tetrahydro-3-oxo-quinoxalinyl,        1,2,3,4-tetrahydro-2,3-dioxo-quinoxalinyl,        1,2-dihydro-1-oxo-phthalazinyl,        1,2,3,4-tetrahydro-1,4-dioxo-phthalazinyl, chromanyl,        coumarinyl, 2,3-dihydro-benzo[1,4]dioxinyl,        3,4-dihydro-3-oxo-2H-benzo[1,4]oxazinyl,    -   and wherein the above-mentioned (het)aryl groups are optionally        substituted with one or two R¹⁰ which may be identical or        different,

R⁵ and R⁶, which may be identical or different, denote halogen,C₁₋₃-alkyl, C₂₋₃-alkynyl, trifluormethyl, hydroxy, C₁₋₃-alkyloxy, cyano,or

R⁵ together with R⁶, if bound to adjacent carbon atoms, may additionallybe methylenedioxy, difluoromethylenedioxy, ethylenedioxy, C₃₋₅-alkylene,or

R⁵ together with R⁶, if bound to adjacent carbon atoms, may formtogether with the carbon atoms to which they are attached, a pyrazolo,imidazo, oxazolo, thiazolo, isoxazolo, or isothiazolo ring, thatoptionally are substituted with C₁₋₃-alkyl, trifluoromethyl, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino, hydroxy, C₁₋₃-alkyloxy,

R⁷ denotes fluorine, chlorine, bromine, iodine,

-   -   C₁₋₄-alkyl, hydroxy, C₁₋₄-alkyloxy,    -   nitro, amino, C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)amino,        pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl, piperidin-1-yl,        2-oxo-piperidin-1-yl, morpholin-4-yl, 3-oxo-morpholin-4-yl,        piperazin-1-yl, 2-oxo-piperazin-1-yl, 3-oxo-piperazin-1-yl,        4-(C₁₋₄-alkyl)-pi-perazin-1-yl,        4-(C₁₋₄-alkylcarbonyl)-piperazin-1-yl,        4-(C₃₋₆-cycloalkylcarbonyl)-piperazin-1-yl,        4-(C₁₋₄-alkyloxycarbonyl)-piperazin-1-yl,        4-(C₁₋₄-alkylsulfonyl)-piperazin-1-yl,        2-oxo-4-(C₁₋₄-alkyl)-piperazin-1-yl,        3-oxo-4-(C₁₋₄-alkyl)-piperazin-1-yl,    -   C₁₋₄-alkyl-carbonylamino, (het)aryl-carbonylamino,        (het)aryl-C₁₋₄-alkyl-carbonylamino, C₁₋-alkyloxy-carbonylamino,        aminocarbonylamino, C₁₋₄-alkyl-aminocarbonylamino,        di-(C₁₋₄-alkyl)aminocarbonylamino,        pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonylamino,        morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino,        4-(C₁₋₄-alkyl)-piperazin-1-yl-carbonylamino,        C₁₋₄-alkyl-sulfonylamino, aminosulfonylamino,        C₁₋₄-alkyl-amino-sulfonylamino,        di-(C₁₋₄-alkyl)amino-sulfonylamino,        pyrrolidin-1-yl-sulfonylamino, piperidin-1-yl-sulfonylamino,        morpholin-4-yl-sulfonylamino, piperazin-1-yl-sulfonyl-amino,        4-(C₁₋₄-alkyl)-piperazin-1-yl-sulfonylamino,        (C₁₋₄-alkyloxy-carbonylamino)-carbonylamino,        (het)arylsulfonylamino, (het)aryl-C₁₋₄-alkyl-sulfonylamino,    -   N—(C₁₋₄-alkyl)-C₁₋₄-alkyl-carbonylamino,        N—(C₁₋₄-alkyl)-(het)arylcarbonylamino,        N—(C₁₋₄-alkyl)-(het)aryl-C₁₋₄-alkyl-carbonylamino,        N—(C₁₋₄-alkyl)-C₁₋₄-alkyloxy-carbonylamino,        N-(aminocarbonyl)-C₁₋₄-alkylamino,        N—(C₁₋₄-alkyl-aminocarbonyl)-C₁₋₄-alkylamino,        N-[di-(C₁₋₄-alkyl)aminocarbonyl]-C₁₋₄-alkylamino,        N—(C₁₋₄-alkyl)-C₁₋₄-alkyl-sulfonylamino,        N—(C₁₋₄-alkyl)-(het)arylsulfonylamino,        N—(C₁₋₄-alkyl)-(het)aryl-C₁₋₄-alkyl-sulfonylamino,    -   oxo-imidazolidin-1-yl, 2,4-dioxo-imidazolidin-1-yl,        2,5-dioxo-imidazolidin-1-yl, 2-oxo -hexahydropyrimidin-1-yl,        wherein the nitrogen atom in position 3 of the aforementioned        groups is optionally substituted with methyl or ethyl,    -   cyano, (hydroxyimino)aminomethyl,        (C₁₋₄-alkyloxyimino)aminomethyl, carboxy,        C₁₋₄-alkyloxy-carbonyl, aminocarbonyl, C₁₋₄-alkyl-aminocarbonyl,        di-(C₁₋₄-alkyl)-amino -carbonyl, pyrrolidin-1-yl-carbonyl,        piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl,        piperazin-1-yl-carbonyl, 4-(C₁₋₄-alkyl)-piperazin-1-yl-carbonyl,    -   C₁₋₄-alkyl-carbonyl, (het)aryl-carbonyl,    -   carboxy-C₁₋₄-alkyl, C₁₋₄-alkyloxy-carbonyl-C₁₋₄-alkyl,        cyano-C₁₋₄-alkyl, aminocarbonyl -C₁₋₄-alkyl,        C₁₋₄-alkyl-aminocarbonyl-C₁₋₄-alkyl,        di-(C₁₋₄-alkyl)-aminocarbonyl-C₁₋₄-alkyl,        pyrrolidin-1-yl-carbonyl-C₁₋₄-alkyl,        piperidin-1-yl-carbonyl-C₁₋₄-alkyl, morpholin-4-yl        -carbonyl-C₁₋₄-alkyl, piperazin-1-yl-carbonyl-C₁₋₄-alkyl,        4-(C₁₋₄-alkyl)-piperazin-1-yl -carbonyl-C₁₋₄-alkyl,    -   carboxy-C₁₋₄-alkyloxy, C₁₋₄-alkyloxy-carbonyl-C₁₋₄-alkyloxy,        cyano-C₁₋₄-alkyloxy, amino -carbonyl-C₁₋₄-alkyloxy,        C₁₋₄-alkyl-aminocarbonyl-C₁₋₄-alkyloxy, di-(C₁₋₄-alkyl)-amino        -carbonyl-C₁₋₄-alkyloxy,        pyrrolidin-1-yl-carbonyl-C₁₋₄-alkyl-oxy,        piperidin-1-yl-carbonyl-C₁ ₋₄-alkyloxy,        morpholin-4-yl-carbonyl-C₁₋₄-alkyl-oxy,        piperazin-1-yl-carbonyl-C₁₋₄-alkyloxy,        4-(C₁₋₄-alkyl)-piperazin-1-yl-carbonyl-C₁₋₄-alkyloxy,    -   hydroxy-C₁₋₄-alkyl, C₁₋₄-alkyloxy-C₁₋₄-alkyl, amino-C₁₋₄-alkyl,        C₁₋₄-alkylamino-C₁₋₄-alkyl, di-(C₁₋₄-alkyl)-amino-C₁₋₄-alkyl,        pyrrolidin-1-yl-C₁₋₄-alkyl, C₁₋₄-alkylcarbonyl-amino-C₁₋₄-alkyl,        N—(C₁₋₄-alkyl)-C₁₋₄-alkylcarbonyl-amino-C₁₋₄-alkyl,    -   2-oxo-pyrrolidin-1-yl-C₁₋₄-alkyl, piperidin-1-yl-C₁₋₄-alkyl,        2-oxo-piperidin-1-yl-C₁₋₄-alkyl, morpholin-4-yl-C₁₋₄-alkyl,        3-oxo-morpholin-4-yl-C₁₋₄-alkyl, piperazin-1-yl-C₁₋₄-alkyl,        2-oxo-piperazin-1-yl-C₁₋₄-alkyl,        3-oxo-piperazin-1-yl-C₁₋₄-alkyl, 4-(C₁₋₄-alkyl)-piperazin        -1-yl-C₁₋₄-alkyl,        2-oxo-4-(C₁₋₄-alkyl)-piperazin-1-yl-C₁₋₄-alkyl,        3-oxo-4-(C₁₋₄-alkyl)-piperazin-1-yl-C₁₋₄-alkyl,    -   hydroxy-C₁₋₄-alkyloxy, C₁₋₄-alkyloxy-C₁₋₄-alkyloxy,        C₁₋₄-alkylsulfanyl-C₁₋₄-alkyloxy,        C₁₋₄-alkylsulfinyl-C₁₋₄-alkyloxy,        C₁₋₄-alkylsulfonyl-C₁₋₄-alkyloxy, amino-C₁₋₄-alkyloxy,        C₁₋₄-alkylamino-C₁₋₄-alkyloxy,        di-(C₁₋₄-alkyl)-amino-C₁₋₄-alkyloxy,        pyrrolidin-1-yl-C₁₋₄-alkyloxy,        2-oxo-pyrrolidin-1-yl-C₁₋₄-alkyloxy,        piperidin-1-yl-C₁₋₄-alkyloxy,        2-oxo-piperidin-1-yl-C₁₋₄-alkyloxy,        morpholin-4-yl-C₁₋₄-alkyloxy,        3-oxo-morpholin-4-yl-C₁₋₄-alkyloxy,        piperazin-1-yl-C₁₋₄-alkyloxy,        2-oxo-piperazin-1-yl-C₁₋₄-alkyloxy,        3-oxo-piperazin-1-yl-C₁₋₄-alkyloxy,        4-(C₁₋₄-alkyl)-piperazin-1-yl-C₁₋₄-alkyloxy,        2-oxo-4-(C₁₋₄-alkyl)-piperazin-1-yl-C₁₋₄-alkyloxy,        3-oxo-4-(C₁₋₄-alkyl)-piperazin-1-yl-C₁₋₄-alkyloxy,    -   C₁₋₄-alkylsulfanyl, C₁₋₄-alkysulfinyl, C₁₋₄-alkylsulfonyl,        C₁₋₄-alkylsulfonyloxy, (het)arylsulfonyl, (het)arylsulfonyloxy,        trifluoromethylsulfanyl, trifluoromethylsulfinyl, trifluoro        -methylsulfonyl, C₃₋₆-cycloalkylsulfanyl,        C₃₋₆-cycloalkylsulfinyl, C₃₋₆-cycloalkylsulfonyl,        C₃₋₆-cycloalkyl-C₁₋₃-alkylsulfanyl,        C₃₋₆-cycloalkyl-C₁₋₃-alkylsulfinyl,        C₃₋₆-cycloalkyl-C₁₋₃-alkylsulfonyl,    -   aminosulfonyl, C₁₋₄-alkyl-aminosulfonyl,        di-(C₁₋₄-alkyl)-aminosulfonyl, pyrrolidin-1-yl -sulfonyl,        piperidin-1-yl-sulfonyl, morpholin-4-yl-sulfonyl,        piperazin-1-yl-sulfonyl, 4-(C₁₋₄-alkyl)-piperazin-1-yl-sulfonyl,    -   difluoromethyl, trifluoromethyl, difluoromethoxy,        trifluoromethoxy,    -   2,2,2-trifluoro-1-hydroxyethyl,        2,2,2-trifluoro-1-hydroxy-1-methylethyl,        2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl,    -   C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyloxy,    -   hydroxy-C₄₋₆-cycloalkyl, C₁₋₃-alkyloxy-C₃₋₆-cycloalkyl,    -   C₃₋₆-cycloalkyl-C₁₋₃-alkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyloxy,    -   (het)aryl, (het)aryloxy, (het)aryl-C₁₋₃-alkyl,        (het)aryl-C₁₋₃-alkyloxy, (het)aryloxy-C₁₋₃-alkyl, or    -   tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,        tetrahydropyran-4-yloxy, tetrahydro -furanyl-C₁₋₃-alkyloxy,        tetrahydropyranyl-C₁₋₃-alkyloxy,

wherein the above-mentioned (het)aryl is defined as describedhereinbefore,

R⁸ and R⁹, which may be identical or different, are halogen, C₁₋₃-alkyl,trifluormethyl, hydroxy, C₁₋₃-alkyloxy, cyano, or

R⁸ together with R⁹, if bound to adjacent carbon atoms, may additionallybe methylenedioxy, difluoromethylenedioxy, ethylenedioxy, C₃₋₅-alkylene,or

R⁸ together with R⁹, if bound to adjacent carbon atoms, may also formtogether with the carbon atoms to which they are attached, a benzo,pyrido, pyrimido, pyrazino, pyridazino, pyrazolo, imidazo, triazolo,oxazolo, thiazolo, isoxazolo, or isothiazolo ring, that all optionallyare substituted with one L and/or one or two substituents independentlyselected from halogen, C₁₋₃-alkyl, trifluoromethyl, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino, hydroxy, C₁₋₃-alkyloxy,

L is L¹ or L² and L¹ denotes halogen, C₁₋₆-alkyl, hydroxy-C₁₋₄-alkyl,C₁₋₃-alkyloxy-C₁₋₃-alkyl, C₃ ₋₆-cycloalkyl, hydroxy-C₄₋₆-cycloalkyl,C₁₋₃-alkyloxy-C₃₋₆-cycloalkyl, azetidinyl, 1-(C₁₋₃-alkyl) -azetidinyl,1-(C₁₋₃-alkylcarbonyl)-azetidinyl, pyrrolidinyl,1-(C₁₋₃-alkyl)-pyrrolidinyl, 1-(C₁₋₃-alkylcarbonyl)-pyrrolidinyl,piperidinyl, 1-(C₁₋₃-alkyl)-piperidinyl, 1-(C₁₋₃-alkylcarbonyl)-piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, difluoromethyl,trifluoromethyl, cyano, nitro, amino, acetylamino, methylsulfonylamino,carboxy, C₁₋₄-alkyloxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, aminosulfonyl, methylsulfanyl,methylsulfinyl, methylsulfonyl, hydroxy, C₁₋₃-alkyloxy, difluoromethoxy,or trifluoromethoxy,

L² denotes phenyl, or

pyrrolyl, furanyl, thienyl, pyridyl, where in any of these groups 1 or 2CH are optionally replaced by N atoms, or

1,2-dihydro-2-oxo-pyridinyl, 1,4-dihydro-4-oxo-pyridinyl,2,3-dihydro-3-oxo-pyridazinyl, 1,2,3,6-tetrahydro-3,6-dioxo-pyridazinyl,1,2-dihydro-2-oxo-pyrimidinyl, 3,4-dihydro-4-oxo -pyrimidinyl,1,2,3,4-tetrahydro-2,4-dioxo-pyrimidinyl, or1,2-dihydro-2-oxo-pyrazinyl,

wherein each of the groups mentioned hereinbefore under L² is optionallysubstituted with one or two groups independently selected from fluorine,chlorine, C₁₋₃-alkyl, difluoromethyl, trifluoromethyl, cyano, amino,acetylamino, methylsulfonylamino, carboxy, C₁₋₄-alkyl -oxycarbonyl,aminocarbonyl, C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,hydroxy, C₁₋₃-alkyloxy, difluoromethoxy, and trifluoromethoxy,

R¹⁰ is R^(10′) or R^(10″) and

R^(10′) denotes halogen, C₁₋₃-alkyl, difluoromethyl, trifluoromethyl,cyano, nitro, amino, acetylamino, methylsulfonylamino, carboxy,C₁₋₄-alkyloxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, aminosulfonyl, methylsulfanyl,methylsulfinyl, methylsulfonyl, hydroxy, C₁₋₃-alkyloxy, difluoromethoxy,or trifluoromethoxy,

R^(10″) denotes pyrrolyl, furanyl, thienyl, pyridyl, wherein in any ofthese groups 1 or 2 CH optionally are replaced by N atoms, or

indolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl,wherein in any of these groups 1 to 3 CH optionally are replaced by Natoms, or

phenyl, naphthyl, tetrazolyl, 1,2-dihydro-2-oxo-pyridinyl,1,4-dihydro-4-oxo-pyridinyl, 2,3-di -hydro-3-oxo-pyridazinyl,1,2,3,6-tetrahydro-3,6-dioxo-pyridazinyl, 1,2-dihydro-2-oxo-pyrimidinyl,3,4-dihydro-4-oxo-pyrimidinyl, 1,2,3,4-tetrahydro-2,4-dioxo-pyrimidinyl,1,2-dihydro-2-oxo-pyrazinyl, 1,2,3,4-tetrahydro-2,3-dioxo-pyrazinyl,2,3-dihydro-2-oxo-indolyl, 2,3-dihydro -benzofuranyl,2,3-dihydro-2-oxo-1H-benzimidazolyl, 2,3-dihydro-2-oxo-benzoxazolyl,1,2-dihydro-2-oxo-quinolinyl, 1,4-dihydro-4-oxo-quinolinyl,1,2-dihydro-1-oxo-isoquinolinyl, 1,4-dihydro-4-oxo-cinnolinyl,1,2-dihydro-2-oxo-quinazolinyl, 1,4-dihydro-4-oxo-quinazolinyl,1,2,3,4-tetrahydro-2,4-dioxo-quinazolinyl,1,2-dihydro-2-oxoquinoxalinyl, 1,2,3,4-tetrahydro-3-oxo-quinoxalinyl,1,2,3,4-tetrahydro-2,3-dioxo-quinoxalinyl,1,2-dihydro-1-oxo-phthalazinyl,1,2,3,4-tetrahydro-1,4-dioxo-phthalazinyl, chromanyl, coumarinyl,2,3-dihydro-benzo[1,4]dioxinyl, or3,4-dihydro-3-oxo-2H-benzo[1,4]oxazinyl,

and wherein any of the groups mentioned hereinbefore under R^(10″)optionally are substituted independently with one or two groups selectedfrom halogen, C₁₋₃-alkyl, difluoromethyl, trifluoromethyl, cyano, nitro,amino, acetylamino, methylsulfonylamino, carboxy,C₁₋₄-alkyl-oxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, aminosulfonyl, methylsulfanyl,methylsulfinyl, methylsulfonyl, hydroxy, C₁₋₃-alkyloxy, difluoromethoxy,and trifluoromethoxy,

X denotes CH or N,

m, n, o denote 0, 1 or 2,

and wherein the bicyclic core structure of general formula I isoptionally substituted independently with R¹¹ to R¹⁴, wherein

-   -   R¹¹ denotes fluorine, C₁₋₄-alkyl, (het)aryl, hydroxy,        C₁₋₄-alkyloxy, cyano, carboxy, C₁₋₄-alkyloxycarbonyl,        aminocarbonyl, C₁₋₄-alkylamino-carbonyl,        di-(C₁₋₄-alkyl)-aminocarbonyl, hydroxy-C₁₋₄-alkyl or        C₁₋₃-alkyloxy-C₁₋₄-alkyl,    -   wherein (het)aryl is as described hereinbefore,    -   R¹² denotes fluorine or C₁₋₄-alkyl, and    -   R¹³ and R¹⁴, which may be identical or different, denote        C₁₋₄-alkyl,

and

whilst the above-mentioned alkyl or alkylene moieties are branched orunbranched,

the tautomers, the stereoisomers thereof, the mixtures thereof, and thesalts thereof,

while the compounds comprised by the formulae II.1 to II.8

wherein

-   R is any substituent,-   M¹ is C₁₋₄-alkyl,-   M² and M³ independently of each other are hydrogen or C₁₋₄-alkyl,-   M⁴ is hydrogen or hydroxy,-   M⁵ is hydrogen or hydroxy, and-   M⁶ denotes phenyl, which may be substituted with one to three    substituents selected from the group consisting of halogen, hydroxy,    alkyl, nitro, cyano, trifluoromethyl, methoxy,    -   naphthyl or biphenylyl, which may be substituted with one to        three substituents selected from the group consisting of        halogen, alkyl, nitro, cyano, trifluoromethyl, methoxy,    -   pyridyl, which may be substituted with halogen, alkyl, nitro,        cyano, trifluoromethyl, methoxy, and NR′R″, where R′ and R″ are        each independently hydrogen or alkyl, or form together with the        nitrogen atom a 3- to 7-membered alicyclic ring optionally        having a double bond,    -   quinolinyl, isoquinolinyl, 4-cyclohexylphenyl,        4-oxo-4H-chromenyl, indolyl, benzothiophenyl, benzofuranyl,        5,6,7,8-tetrahydro-naphthalen-1-yl,        5,6,7,8-tetrahydro-naphthalen-2-yl, furanyl, methylfuranyl,        ethylfuranyl, methoxymethylfuranyl, thienyl, methylthienyl, or        ethylthienyl,

wherein

-   M¹ is C₁₋₄-alkyl,-   M² is hydrogen or C₁₋₄-alkyl,-   M⁶ denotes 2-acetoxy-phenyl, 2-ethylamino-phenyl,    2-phenylamino-phenyl, 2-(2,3-dimethyl-phenylamino)-phenyl,    2-(3-methylsulfanylphenylamino)-phenyl, or pyridyl,

wherein

-   R is hydrogen, C₁₋₆-alkyl-   M¹ is hydrogen or C₁₋₄-alkyl,-   M⁴ is hydrogen or hydroxy,-   M⁶ is phenyl, methylphenyl, or methoxyphenyl,

are excluded.

The compounds of general formula I according to the invention and thephysiologically acceptable salts thereof have valuable pharmacologicalproperties, particularly an inhibitory effect on the enzyme11β-hydroxysteroid dehydrogenase (HSD) 1.

The first aspect of the invention also relates to the physiologicallyacceptable salts of the compounds of general formula I with inorganic ororganic acids, except for the salts of the compounds comprised by theformulae II.1 to II.8.

In a second aspect this invention relates to pharmaceuticalcompositions, containing at least one compound of general formula I,except for the compounds comprised by the formulae II.1 to II.8, or aphysiologically acceptable salt according to the invention, optionallytogether with one or more inert carriers and/or diluents.

In a third aspect this invention relates to the compounds according togeneral formula I, including the compounds comprised by the formulaeII.1 to II.8, or the physiologically acceptable salts thereof, fortreatment or prevention of diseases or conditions which can beinfluenced by inhibiting the enzyme 11β-hydroxysteroid dehydrogenase(HSD) 1, such as metabolic disorders.

In a fourth aspect this invention relates to the use of at least onecompound according to general formula I, including the compoundscomprised by the formulae II.1 to II.8, or one of the physiologicallyacceptable salts thereof for preparing a pharmaceutical compositionwhich is suitable for the treatment or prevention of diseases orconditions which can be influenced by inhibiting the enzyme11β-hydroxysteroid dehydrogenase (HSD) 1, such as metabolic disorders.

In a fifth aspect the invention relates to a process for preparing apharmaceutical composition according to the invention, characterized inthat a compound of general formula I, except for the compounds comprisedby the formulae II.1 to II.8, or one of the physiologically acceptablesalts thereof is incorporated in one or more inert carriers and/ordiluents by a non-chemical method.

In a sixth aspect the present invention relates to a process forpreparing the compounds of general formula I, except for the compoundscomprised by the formulae II.1 to II.8, characterized in that

in order to prepare compounds of general formula I which are defined ashereinbefore and hereinafter,

a compound of general formula III

wherein

-   the groups R², R³ and X, m, n and o are defined as hereinbefore and    hereinafter;-   is reacted with R¹—CO—Y, optionally prepared in situ from the    corresponding carboxylic acid, wherein-   Y is a leaving group and in particular    -   denotes fluorine, chlorine, bromine, cyano, C₁₋₁₀-alkoxy,        C₁₋₆-alkylsulfanyl, C₂₋₄-alkenyl-oxy, C₂₋₄-alkynyloxy,        oxyarylotriazol, oxyheteroarylotriazol, heteroaryl,        succinyl-N-oxy, C₁₋₄-alkylcarbonyloxy,        di-(C₁₋₄-alkyl)aminocarbonyloxy, pyrrolylcarbonyloxy,        piperidinyl-carbonyloxy, morpholinylcarbonyloxy,        tri-(C₁₋₄-alkyl)carbamimidoyloxy,        N,N,N′,N′-tetra-(C₁₋₄-alkyl)uronyl, N,N′-dicyclohexyluronyl,        di-(C₁₋₄-alkyloxy)-phosphoryloxy,        di-(di-C₁₋₄-alkylamino)-phosphoryloxy,        dipyrrolidinophosphoryloxy, arylsulfanyl, heteroarylsulfanyl,        aryloxy, or heteroaryloxy,    -   while the alkyl, alkenyl, and alkynyl groups mentioned in the        definition of the above groups, either alone or as part of        another group, may be mono- or polysubstituted with fluorine,        chlorine, C₁₋₃-alkyl, or C₁₋₃-alkoxy,    -   while the aryl groups mentioned in the definition of the above        groups, either alone or as part of another group, denote phenyl        or naphthyl groups and the heteroaryl groups mentioned in the        definition of the above groups, either alone or as part of        another group, denote pyridinyl, pyrimidinyl, triazinyl,        imidazolyl, pyrazolyl, triazolyl, tetrazolyl, whilst both the        aryl and heteroaryl groups optionally are independently mono or        polysubstituted with fluorine, chlorine, bromine, C₁₋₃-alkyl,        C₁₋₃-alkyloxy, nitro, cyano, or di-(C₁₋₃-alkyl)amino groups,

and R¹ is defined as hereinbefore and hereinafter,

optionally in the presence of a base or another additive;

and, if necessary any protective group used in the reactions describedabove is cleaved concurrently or subsequently;

if desired a compound of general formula I obtained as described aboveis resolved into its stereoisomers;

if desired a compound of general formula I thus obtained is convertedinto the salts thereof, particularly for pharmaceutical use into thephysiologically acceptable salts thereof.

In a seventh aspect the present invention relates to novel compounds offormulae IIIa to IIIg, representing subgeneric structures of formulaIII, including their tautomers, their stereoisomers, and the saltsthereof, which are suitable as intermediates in the synthesis ofcompounds of formula I, characterised by

-   formula

wherein the bicyclic substructure of formula IIIa(2-aza-bicyclo[3.3.1]non-6-ene, comprised by the core structure offormula I) is optionally substituted with one to three methyl groups andwherein A denotes an heteroarylo ring that is annelated to thepolycyclic scaffold in formula IIIa via two adjacent carbon atoms of thebenzo ring and wherein

-   heteroarylo denotes triazolo or C₁₋₃-alkyl-triazolo or-   pyrido, pyrimido, pyrazino, pyridazino, each of them being    optionally substituted with one L and/or one or two substituents    independently selected from fluorine, chlorine, C₁₋₃-alkyl,    trifluoromethyl, hydroxy, C₁₋₃-alkyloxy, or-   pyrazolo, imidazo, N—C₁₋₃-alkyl-imidazo, oxazolo, thiazolo,    isoxazolo, or isothiazolo, each of them being optionally substituted    with one L,-   preferably, heteroarylo denotes triazolo or methyl-triazolo, or-   pyrazino optionally substituted with one L and/or one substituent    selected from fluorine, methyl, and methoxy, or-   imidazo, N-methyl-imidazo, or oxazolo, each of them being optionally    substituted with one L,-   T denotes fluorine, chlorine, hydroxy, C₁₋₃-alkyl, C₁₋₃-alkyloxy,    preferably, fluorine, methyl, hydroxy, and methoxy,-   m denotes 0, 1, or 2, preferably, 0 or 1,-   and wherein L is as defined hereinbefore and hereinafter; and-   formula

wherein the bicyclic substructure of formula IIIb(2-aza-bicyclo[3.3.1]non-6-ene) is optionally substituted with one tothree methyl groups and wherein

-   S¹ denotes fluorine, chlorine, ethyl, propyl, isopropyl,    trifluoromethyl, hydroxy-C₁₋₃-alkyl, cyano, carboxy,    C₁₋₃-alkyloxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,    di-(C₁₋₃-alkyl)aminocarbonyl, C₁₋₃-alkylsulfonyl,-   preferably, S¹ denotes fluorine, cyano, carboxy,    C₁₋₃-alkyloxycarbonyl, aminocarbonyl, methylaminocarbonyl,    dimethylaminocarbonyl, methylsulfonyl,-   n denotes 0, 1, 2, or 3, preferably, 0 or 1,-   and T is as defined hereinbefore; and-   formula

wherein the bicyclic substructure of formula IIIc(2-aza-bicyclo[3.3.1]non-6-ene) is optionally substituted with one tothree methyl groups and wherein

-   S² denotes fluorine, C₁₋₃-alkyl, amino-C₁₋₃-alkyl,    acetylamino-C₁₋₃-alkyl, hydroxy-C₁₋₃-alkyl, C₁₋₃-alkylcarbonyl,    cyano, carboxy, C₁₋₃-alkyloxycarbonyl, aminocarbonyl,    C₁₋₃-alkylamino carbonyl, di-(C₁₋₃-alkyl)aminocarbonyl, amino,    C₁₋₃-alkylcarbonylamino, C₁₋₃-alkylsulfonylami no,    di-(C₁₋₃-alkyl)-aminosulfonyl, or-   phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl,    thiazolyl, or N-methyl-pyridin-2-onyl, each of them being optionally    substituted with one or two groups independently selected from    fluorine, C₁₋₃-alkyl, trifluoromethyl, and C₁₋₃-alkyloxy, or    oxadiazolyl optionally substituted with C₁₋₄-alkyl,-   preferably, S² denotes fluorine, methyl, aminomethyl,    acetylaminomethyl, hydroxyethyl, methylcarbonyl, cyano, carboxy,    C₁₋₃-alkyloxycarbonyl, aminocarbonyl, methylaminocarbonyl,    dimethylaminocarbonyl, amino, acetylamino, methylsulfonylamino,    dimethylaminosulfonyl, or phenyl or oxadiazolyl, each of them being    optionally monosubstituted with methyl,-   and T and n are as defined hereinbefore; and-   formula

wherein the bicyclic substructure of formula IIId(2-aza-bicyclo[3.3.1]non-6-ene) is optionally substituted with one tothree methyl groups and wherein

-   S³ denotes C₁₋₃-alkyl, amino-C₁₋₃-alkyl, hydroxy-C₁₋₄-alkyl,    hydroxy-trifluoromethyl-C₁₋₃-alkyl, C₁₋₄-alkylcarbonyl, cyano,    carboxy, C₁₋₃-alkyloxycarbonyl, aminocarbonyl, C₁₋₃-alkylamino    carbonyl, di-(C₁₋₃-alkyl)aminocarbonyl, C₁₋₃-alkylsulfonyl,    aminosulfonyl, C₁₋₃-alkylamino sulfonyl,    di-(C₁₋₃-alkyl)-aminosulfonyl, tetrazolyl, or-   phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl,    thiazolyl, triazolyl, N—(C₁₋₃-alkyl)-pyridin-2-onyl,    N—(C₁₋₃-alkyl)-pyridazin-3-onyl, each of them being optionally mono-    or disubstituted with substituents independently selected from    fluorine, C₁₋₃-alkyl, trifluorome thyl, and C₁₋₃-alkyloxy, or-   oxadiazolyl optionally substituted with C₁₋₄-alkyl,-   preferably, S³ denotes aminomethyl, hydroxy-C₁₋₃-alkyl,    hydroxy-trifluoromethyl-ethyl, methyl carbonyl, cyano, carboxy,    C₁₋₃-alkyloxycarbonyl, aminocarbonyl, methylaminocarbonyl,    dimethylaminocarbonyl, methylsulfonyl, aminosulfonyl,    methylaminosulfonyl, dimethylamino sulfonyl, tetrazolyl, or-   phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl,    each of them being optionally mono- or disubstituted with methyl, or-   N-methyl-pyridin-2-onyl, N-methyl-pyridazin-3-onyl, oxadiazolyl,    each of them being optionally additionally substituted with methyl,-   and T and n are as defined hereinbefore; and-   formula

wherein the bicyclic substructure of formula IIIe(2-aza-bicyclo[3.3.1]non-6-ene) is optionally substituted with one tothree methyl groups and wherein

-   S⁴ denotes fluorine, ethyl, propyl, isopropyl, trifluoromethyl,    hydroxy-C₁₋₃-alkyl, cyano, carboxy, C₁₋₃-alkyloxycarbonyl,    aminocarbonyl, C₁₋₃-alkylaminocarbonyl,    di-(C₁₋₃-alkyl)aminocarbonyl, nitro, amino, C₁₋₃-alkylcarbonylamino,    C₁₋₃-alkylsulfonylamino, or phenyl, pyridinyl, pyrimidinyl,    pyrazinyl, pyridazinyl, oxazolyl, thiazolyl, pyrrol-1-yl,    N—(C₁₋₃-alkyl)-pyridin-2-onyl, each of them being optionally mono-    or disubstituted with substituents independently selected from    fluorine, C₁₋₃-alkyl, trifluoromethyl, and C₁₋₃-alkyloxy, or-   preferably, S⁴ denotes cyano, nitro, amino, methylsulfonylamino,    pyridinyl, pyrrol-1-yl,-   and T and n are as defined hereinbefore; and-   formulae

wherein the bicyclic substructure of formula IIIf and IIIg(2-aza-bicyclo[3.3.1]non-6-ene) is optionally substituted with one tothree methyl groups and wherein

-   S⁵ denotes hydrogen, C₁₋₄-alkyl, preferably, hydrogen or methyl, and-   S⁶ denotes hydrogen, C₁₋₄-alkyl, preferably, hydrogen or methyl.

Compounds according to the invention obtained by the synthetic routesdescribed may be subsequently converted into other compounds of theinvention by routine processes applicable for conversion of functionalgroups. Examples for subsequent conversion processes are provided in thefollowing paragraphs.

If according to the invention a compound of general formula I isobtained which contains an amino, alkylamino or imino group, this may beconverted by acylation or sulfonylation into a corresponding acyl orsulfonyl compound of general formula I;

-   if a compound of general formula I is obtained which contains a    hydroxy group, this may be converted by acylation or sulfonylation    into a corresponding acyl or sulfonyl compound of general formula I;-   if a compound of general formula I is obtained which contains an    amino, alkylamino or imino group, this may be converted by    alkylation or reductive alkylation into a corresponding alkyl    compound of general formula I;-   if a compound of general formula I is obtained which contains a    nitro group, this may be converted by reduction into a corresponding    amino compound;-   if a compound of general formula I is obtained which contains an    imino group, this may be converted by nitrosation and subsequent    reduction into a corresponding N-amino-imino compound;-   if a compound of general formula I is obtained which contains a    C₁₋₃-alkyloxycarbonyl group, this may be converted by cleavage of    the ester into the corresponding carboxy compound;-   if a compound of general formula I is obtained which contains a    carboxy group, this may be converted by esterification into a    corresponding ester of general formula I;-   if a compound of general formula I is obtained which contains a    carboxy or ester group, this may be converted by reaction with an    amine into a corresponding amide of general formula I;-   if a compound of general formula I is obtained which contains an    aromatic substructure, this may be derivatized with a chlorine,    bromine, or iodine atom or a nitro, sulfonic acid, or acyl group to    a corresponding compound of general formula I by an electrophilic    substitution reaction;-   if a compound of general formula I is obtained which contains an    aromatic amino group, this may be transformed into a corresponding    cyano, fluoro, chloro, bromo, iodo, hydroxy, mercapto, or azido    compound of general formula I by diazotization and subsequent    replacement of the diazo group with cyanide, fluoride, chloride,    bromide, iodide, hydroxide, alkyl or hydrogen sulfide, or azide,    respectively;-   if a compound of general formula I is obtained which contains an    aromatic amino group, this may be converted into a corresponding    aryl derivatized aromatic compound of general formula I by    diazotization and subsequent replacement of the diazo group with an    appropriate aryl nucleophile mediated by a suited transition metal    species; if a compound of general formula I is obtained which    contains an aromatic chloro, bromo, iodo,    trifluoromethylsulfonyloxy, mesyloxy, or tosyloxy group, this may be    converted into a corresponding aryl, alkenyl, alkynyl, or alkyl    derivatized compound of general formula I by replacement of the    respective group by aryl, alkenyl, alkynyl, or alkyl using a    transition metal species mediated process;-   if a compound of general formula I is obtained which contains an    aromatic chloro, bromo, iodo, trifluoromethylsulfonyloxy, mesyloxy,    or tosyloxy group, this may be replaced for hydrogen to give a    corresponding aromatic compound of general formula I;-   if a compound of general formula I is obtained which contains two    adjacent heteroatoms that are amino and hydroxy, amino, or mercapto,    these heteroatoms may be linked via a carboxy carbon atom to form a    cyclic amidine, imino ester, or imino thioester substructure that    may be part of an aromatic ring;-   if a compound of general formula I is obtained which contains a    cyano group, this may be converted into an amino alkyl derivatized    compound of general formula I by reduction;-   if a compound of general formula I is obtained which contains a    cyano group, this may be converted into a N-hydroxycarbamimidoyl    group by the treatment with hydroxylamine;-   if a compound of general formula I is obtained which contains an    N-hydroxycarbamimidoyl group, this may be converted to an oxadiazole    derivatized compound of general formula I by the treatment with a    carboxylic or related group;-   if a compound of general formula I is obtained which contains an    aminocarbonyl group, this may be converted by dehydration into a    corresponding cyano compound of general formula I;-   if a compound of general formula I is obtained which contains a keto    or aldehydic group, this may be converted by reaction with a carbon    nucleophile into a corresponding hydroxy alkyl compound of general    formula I;-   if a compound of general formula I is obtained which contains a keto    or aldehydic group, this may be converted by reduction into a    corresponding hydroxyl compound of general formula I;-   if a compound of general formula I is obtained which contains a    cyano group, this may be converted into a corresponding tetrazolyl    compound of general formula I by reacting with an azide salt or    derivative;-   if a compound of general formula I is obtained which contains a    nitro group, this may be converted by reduction into a corresponding    amino compound; and/or-   if a compound of general formula I is obtained which contains an    amino group, this may be converted to a corresponding pyrrolyl    substituted compound of general formula I by reaction with an    1,4-dicarbonyl compound or a synthon thereof.

The subsequent esterification is optionally carried out in a solvent ormixture of solvents such as methylene chloride, dimethylformamide,benzene, toluene, chlorobenzene, tetrahydro-furan,benzene/tetrahydrofuran or dioxane or particularly advantageously in thecorresponding alcohol optionally in the presence of an acid such ashydrochloric acid or in the presence of a dehydrating agent, e.g.isobutyl chloroformate, thionyl chloride, trimethylchlorosilane,sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorustrichloride, phosphorus pentoxide, N,N′-dicyclohexylcarbodiimide,N,N′-dicyclohexylcarbodiimide/N-hydroxy-succinimide or1-hydroxy-benzotriazole and optionally additionally in the presence of4-dimethylamino-pyridine, N,N′-carbonyldiimidazole ortriphenylphosphine/carbon tetrachloride, conveniently at temperaturesbetween 0 and 150° C., preferably between 0 and 80° C.

The subsequent ester formation may also be carried out by reacting acompound which contains a carboxy group with a corresponding alkylhalide.

The subsequent acylation or sulfonylation is optionally carried out in asolvent or mixture of solvents such as methylene chloride,dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran,benzene/tetrahydrofuran or dioxane with a corresponding acyl or sulfonylderivative optionally in the presence of a tertiary organic base or inthe presence of an inorganic base or in the presence of a dehydratingagent, e.g. in the presence of isobutyl chloroformate, thionyl chloride,trimethylchlorosilane, sulfuric acid, methanesulfonic acid,p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide,N,N′-dicyclohexyl-carbodiimide,N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide or1-hydroxy-benzotriazole and optionally additionally in the presence of4-dimethylamino-pyridine, N,N′-carbonyldiimidazole ortriphenylphosphine/carbon tetrachloride, at temperatures between 0 and150° C., preferably between 0 and 80° C.

The subsequent alkylation is optionally carried out in a solvent ormixture of solvents such as methylene chloride, dimethylformamide,benzene, toluene, chlorobenzene, tetrahydrofuran,benzene/tetrahydrofuran or dioxane with an alkylating agent such as acorresponding halide or sulfonic acid ester, e.g. methyl iodide, ethylbromide, dimethylsulfate, or benzyl chloride, optionally in the presenceof a tertiary organic base or in the presence of an inorganic base attemperatures between 0 and 150° C., preferably between 0 and 100° C.

The subsequent reductive alkylation is carried out with a correspondingcarbonyl compound such as e.g. formaldehyde, acetaldehyde,propionaldehyde, acetone or butyraldehyde in the presence of a complexmetal hydride such as sodium borohydride, lithium borohydride, sodiumtriacetoxyborohydride or sodium cyanoborohydride conveniently at a pH of6-7 and at ambient temperature or using hydrogen in the presence of atransition metal catalyst, e.g. palladium/charcoal at a hydrogenpressure of 1 to 5 bar. The methylation may also be carried out in thepresence of formic acid as reducing agent at elevated temperature, e.g.between 60 and 120° C.

The subsequent reduction of a nitro group is carried out, for example,with hydrogen and a catalyst such as palladium on carbon, platinumdioxide or Raney nickel, or using other reducing agents such as iron orzinc in the presence of an acid such as acetic acid.

The subsequent nitrosation of an imino group followed by reduction toobtain the N-amino-imino compound is carried out, for example, with analkyl nitrite such as isoamyl nitrite to form the N-nitroso-iminocompound that is then reduced to the N-amino-imino compound using, forexample, zinc in the presence of an acid such as acetic acid.

The subsequent cleaving of a C₁₋₃-alkyloxycarbonyl group to obtain thecarboxy group is carried out, for example, by hydrolysis with an acidsuch as hydrochloric acid or sulfuric acid or an alkali metal hydroxidesuch as lithium hydroxide, sodium hydroxide, or potassium hydroxide.

The subsequent amide formation is carried out by reacting acorresponding reactive carboxylic acid derivative with a correspondingamine optionally in a solvent or mixture of sol-vents such as methylenechloride, dimethylformamide, benzene, toluene, chlorobenzene,tetrahydrofuran, benzene/tetrahydrofuran or dioxane, while the amineused may also serve as solvent, optionally in the presence of a tertiaryorganic base or in the presence of an inorganic base or with acorresponding carboxylic acid in the presence of a dehydrating agent,e.g. in the presence of isobutyl chloroformate, thionyl chloride,trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide,N,N′-dicyclohexylcarbodiimide,N,N′-dicyclo-hexylcarbodiimide/N-hydroxysuccinimide or1-hydroxy-benzotriazole and optionally additionally in the presence of4-dimethylamino-pyridine, N,N′-carbonyldiimidazole ortriphenyl-phosphine/carbon tetrachloride, conveniently at temperaturesbetween 0 and 150° C., preferably between 0 and 80° C.

The subsequent introduction of a chlorine, bromine, or iodine atom ontoan aromatic sub-structure may be carried out by reacting the aromaticcompound with an appropriate electrophile of the halogen atom. Suitedchlorine and bromine electrophiles may be e.g. N-halo-succinimide, HOCl,HOBr, tertBuOCl, tertBuOBr, chlorine, bromine, dibromoisocyanuric acid,pyridinium dichlorobromate, pyridinium tribromide, or sulfuryl chloridethat may be used alone or in combination with an acid, e.g. hydrochloricacid, hydrobromic acid, tetrafluoroboric acid, triflic acid, sulfuricacid, or acetic acid, or a Lewis acid, e.g. iron(III) halide,borontrifluoride hydrate, borontrifluoride etherate, or aluminum halide.Further useful combinations may be LiBr and ceric ammonium nitrate, KClor KBr with Oxone®, or KBr and sodium per-borate. Suited iodineelectrophiles may be generated from iodine combined with an oxidizingagent such as nitric acid, sulfur trioxide, manganese dioxide, HIO₃,hydrogen peroxide, sodium periodate, peroxydisulfates, and Oxone®.Further suited iodine electrophiles may be e.g. iodine chloride,dichloroiodates, and N-iodosuccinimide. These iodine electrophiles maybe used without an additive or in the presence of an acid such as e.g.acetic acid, trifluoroacetic acid, or sulfuric acid, or a Lewis acidsuch as borontrifluoride hydrate, or copper salts. If a nitro group isto be introduced appropriate nitro electrophiles may be generated from,for example, nitric acid, acetyl nitrate, ceric ammonium nitrate, sodiumnitrate, N₂O₅, alkyl nitrate, and nitronium tetrafluoroborate. Some ofthese reagents may be used without an additive, though, several of themare better used in combination with an acid, e.g. sulfuric acid ortriflic acid, acetic anhydride, trifluoroacetic anhydride, Lewis acid,e.g. ytterbium triflate or iron acetate, P₂O₅, or a base. The SO₃H groupmay be introduced by reacting the aromatic compound with, for example,concentrated sulfuric acid, SO₃, ClSO₃H, or ClSO₂NMe₂ combined withindium triflate. Acylating the aromatic part is conducted using an acylelectrophile that may be generated from the respective acyl halide, e.g.chloride, or acyl anhydride and a Lewis acid such as e.g. aluminumhalide, diethylaluminum halide, indium halide, iron(III) halide, tin(IV)halide, borontrifluoride, titanium(IV) halide, or a Brønsted acid, e.g.sulfuric acid or triflic acid. The formyl group is best introduced usingthe so-called Vilsmeier or Vilsmeier-Haack conditions: dialkylformamidecombined with phosgene, thionyl chloride, POCl₃, or oxalyl chloride.Preferred solvents for the electrophilic substitutions described maydiffer depending on the electrophile employed; in the following somemore generally applicable are mentioned: methylene chloride,dichloroethane, chlorobenzene, dichlorobenzene, ether, fluorinatedhydrocarbons, hexanes, quinoline, or acetonitrile. The temperaturespreferably applied range from 0 to 180° C.

The subsequent replacement of an aromatic amino group is initiated bydiazotization of the amino group using a nitrous acid or nitrosoniumsource or equivalent such as a nitrite salt combined with an acid, e.g.sodium nitrite and hydrochloric acid, nitrosonium tetrafluoro-borate, oran alkylnitrite, e.g. tertbutylnitrite or isoamylnitrite. Thediazotization is optionally carried out in methylene chloride,dichloroethane, dimethylformamide, N-methylpyrrolidinone, benzene,toluene, chlorobenzene, tetrahydrofuran, water, ethyl acetate, alcohol,ether, dimethoxyethane, dioxane or mixtures thereof at temperaturesbetween −10° C. and 100° C. (diazotization of amino groups is detailedin, for example, Angew. Chem. Int. Ed. 1976, 15, 251). The subsequentdisplacement of the diazo group for a cyano group, chlorine, or bromineusing cuprous cyanide, chloride, or bromide, respectively, is known asthe Sand-meyer reaction (see e.g. March's Advanced Organic Chemistry,Michael B. Smith and Jerry March, John Wiley & Sons Inc., 6. Ed., NewJersey, 2007 and references quoted therein); the reaction is optionallyconducted between −10° C. and 120° C. in one of the solvents or mixturesmentioned above. The replacement of the diazo group for a fluorine atommay be achieved with a tetrafluoroborate salt or acid and heating to 20to 160° C.; the reaction is known as the Schiemann reaction. Iodine maybe introduced by treatment of the diazo compound with an iodide salt,e.g. sodium iodide, preferably using water or an aqueous solvent mixtureat temperatures between 0 and 120° C. The diazo group is replaced forhydroxy using water or an aqueous solvent mixture at temperaturesbetween 0 and 180° C. The reaction usually works without furtheradditives but the addition of cuprous oxide or strong acid may beadvantageous. Mercapto or alkylmercapto may be introduced via theircorresponding disulfide salts or dialkyldisulfides at temperaturesbetween 0 and 120° C.; depending on the sulfur species used an inertsolvent or aqueous solvent system may be preferred (see e.g. Synth.Commun. 2001, 31, 1857 and references quoted therein).

The subsequent replacement of an aromatic amino group by an aryl groupmay be carried out via the corresponding diazo compound obtainable asdescribed above. The reaction with an aryl nucleophile, preferably anaryl boronic acid, boronic ester, trifluoroborate, zinc halide, orstannane, is conducted in the presence of a transition metal speciesderived from palladium, nickel, rhodium, copper, or iron, preferablypalladium. The active catalyst may be a complex of the transition metalwith ligands such as e.g. phosphines, phosphites, imdiazole carbenes,imidazolidine carbenes, dibenzylideneacetone, allyl, or nitriles, anelemental form of the transition metal such as palladium on carbon ornanoparticles, or salts such as chloride, bromide, acetate, ortrifluoroacetate. In these reactions the diazo compound is preferablyemployed as its tetrafluoroborate salt optionally in methylene chloride,dimethylformamide, N-methylpyrrolidinone, benzene, toluene,tetrahydrofuran, water, ethyl acetate, alcohol, ether, dimethoxyethane,dioxane, or mixtures thereof at temperatures between 10° C. and 180° C.,preferably between 20° C. and 140° C.

The subsequent replacement of an aromatic chloro, bromo, iodo atom or anaromatic trifluoromethylsulfonyloxy, mesyloxy, or tosyloxy group for anaryl, alkenyl, alkynyl, or alkyl residue is preferably mediated by atransition metal species derived from palladium, nickel, rhodium,copper, or iron. The active catalyst may be a complex of the transitionmetal with ligands such as e.g. phosphines (e.g. tritertbutylphosphine,tricyclohexylphosphine, substituted biphenyldicyclohexylphosphines,substituted biphenylditertbutylphosphines, triphenyl-phosphine,tritolylphosphine, trifurylphosphine,1,1′-bis(diphenylphosphino)ferrocene), phosphites, imdiazole carbenes,imidazolidine carbenes, dibenzylideneacetone, allyl, or nitriles, anelemental form of the transition metal such as palladium on carbon ornanoparticles of iron or palladium, or a salt such as fluoride,chloride, bromide, acetate, triflate, or trifluoroacetate. Thereplacement is preferably conducted with a trifluoroborate, boronicacid, or boronic ester (Suzuki or Suzuki-type reaction), zinc halide(Negishi or Negishi-type reaction), stannane (Stille or Stille-typereaction), silane (Hiyama or Hiyama-type reaction), magnesium halide(Kumada or Kumada-type reaction) of the aryl, alkenyl, or alkyl residueto be introduced. The terminal alkyne is preferably used as it is or asthe zinc acetylide derivative. Depending on the electrophilic andnucleophilic reaction partners additives such as halide salts, e.g.lithium chloride, potassium fluoride, tetrabutylammonium fluoride,hydroxide sources such as potassium hydroxide or potassium carbonate,silver salts such as silver oxide or triflate, copper salts such ascopper chloride or copper thiophenecarboxylate may be advantageous oreven essential. Copper iodide is a preferred additive in the couplingwith a terminal alkyne group (Sonogashira reaction). The couplingreactions are optionally conducted in methylene chloride,dimethylformamide, N-methylpyrrolidinone, benzene, toluene,tetra-hydrofuran, water, ethyl acetate, alcohol, ether,dimethylsulfoxide, dimethoxyethane, dioxane, or mixtures thereof,though, depending on the nucleophile some of them are less or not suitedat all. Preferred temperatures are in the range from −10° C. to 180° C.

The subsequent replacement of an aromatic chlorine, bromine, iodine atomor an aromatic trifluoromethylsulfonyloxy, mesyloxy, or tosyloxy groupfor a hydrogen atom is preferably mediated by a transition metal speciesderived from palladium, nickel, platinum, rhodium, or ruthenium. Theactive catalyst may be a complex of the transition metal with ligands,an elemental form, or a salt of the transition metal as mentioned above.Raney nickel or palladium on carbon are among the preferred catalystspecies. Suited hydrogen sources may be hydrogen, preferably atpressures of 1 to 5 bar, silanes, e.g. trialkoxysilane, boranes,hydrides, e.g. alkali metal borohydride, formic acid, or formates, e.g.ammonium formate. The reactions are preferably carried out in methylenechloride, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone,benzene, toluene, tetrahydrofuran, water, ethyl acetate, alcohol, ether,dimethoxyethane, dioxane, or mixtures thereof at −10° C. to 180° C.,more preferably at 20° C. to 140° C.

The subsequent cyclization of two adjacent heteroatoms is optionallyconducted with a carboxy equivalent such as nitrile, carboxylic chlorideor fluoride, carboxylic acid, ketene, carboxylic ester, or carboxylicthioester. The overall transformation consists of two reaction steps:attachment of the carboxy equivalent to one of the two heteroatomsfollowed by cyclization with the other heteroatom. The first step is anamide formation with the amino functionality that may be carried out asdescribed hereinbefore. The ensuing reaction step, cyclization with thesecond heteroatom, may be accomplished by heating in the presence of anacid, e.g. acetic acid, trifluoroacetic acid, sulfuric acid, orhydrochloric acid, or a base, e.g. sodium hydroxide, sodium ethoxide, orsodium tertbutoxide. The use of dehydrating reagents such as anhydrides,e.g. acetic anhydride, orthoesters, e.g. trimethylorthoformate,thionyl-chloride, phosgene, diphosgene, triphosgene, phosphorousoxychloride, phosphorous penta-chloride, dialkylcarbodiimides,combinations of phosphines, e.g. triphenylphosphine or trialkylphosphinewith dialkyl azodicarboxylates, bromine, iodine, or 1,2-dihaloethanes,e.g. 1,2-dibromotetrafluoroethane, may be advantageous. The reactionsare preferably carried out in inert solvents or mixtures such asmethylene chloride, dichloroethane, benzene, toluene, tetrahydrofuran,ether, or combinations thereof, though, cyclization in the presence ofan acid or a base may also be conducted in water or an alcohol, e.g.methanol, ethanol, isopropanol, or tertbutanol, or combinations withthese solvents. The reactions are carried out at temperatures between 0°C. and 200° C., preferably between 20° C. and 140° C.

The subsequent reduction of a cyano group to obtain an aminomethyl groupis optionally conducted with hydrogen in the presence of a transitionmetal species or with a hydride. Suited transition metals may be derivedfrom palladium, nickel, platinum, rhodium, or ruthenium such as, forexample, palladium on charcoal, palladium hydroxide, platinum oxide, orRaney nickel that may be used in solvents such as ethyl acetate,alcohols, e.g. methanol or ethanol, dichloromethane, tetrahydrofuran,ether, benzene, toluene, dimethylformamide, or N-methylpyrrolidinone athydrogen pressures between 1 and 10 bar, preferably between 1 and 5 bar,and at temperatures between 0 and 180° C., preferably between 20 and120° C. Additives such as acids, e.g. hydrochloric acid, methanesulfonicacid, sulfuric acid, or acetic acid, may be beneficial for thehydrogenation. Appropriate hydride sources may be selected from e.g.borohydrides, e.g. sodium borohydride, potassium trisecbutylborohydride,borane, or lithium triethylborohydride, or alanates, e.g. lithiumaluminum hydride or diisobutylaluminum hydride. Some of these reagentsare best used in combination with nickel chloride or cobalt chloride assodium borohydride. These reagents may be used in e.g. tetrahydrofuran,ether, dioxane, 1,2-dimethoxyethane, dichloromethane,1,2-dichloroethane, benzene, or toluene; some are also compatible withalcoholic solutions. Preferred reaction temperatures range from −80° C.to 160° C., more preferred from −40° C. to 60° C.

The subsequent formation of a N-hydroxycarbamimidoyl group from a cyanogroup may be carried out by the treatment of the cyano compound withhydroxylamine. The reaction is preferably conducted in aqueous oralcoholic solvents at temperatures between 0° C. and 140° C.

The subsequent formation of an oxadiazole from an N-hydroxycarbamimidoylis optionally conducted with a carboxy equivalent such as nitrile,carboxylic chloride or fluoride, carboxylic acid, ketene, carboxylicester, or carboxylic thioester. The transformation is related to theformation of a ring starting from two adjacent heteroatoms describedabove and may be carried out analogously.

The subsequent formation of a cyano group from an amino carbonyl groupis optionally con-ducted by using a dehydrating reagent such as e.g.anhydride, e.g. acetic anhydride, trifluoroacetic anhydride, or triflicanhydride, phosgene, thionyl chloride, oxalyl chloride, POCl₃, PCl₅,P₄O₁₀, triphenylphosphite, or triphenyl- or trialkylphosphine combinedwith tetrachloro-methane, 1,2-dibromotetrafluoroethane, or bromine. Thereactions are preferably carried out in dichloromethane,1,2-dichloroethane, hexanes, ether, dioxane, benzene, toluene,acetonitrile, mixtures thereof, or without a solvent at temperaturesbetween 0° C. and 140° C. Additives such as amines, e.g. pyridine ortriethylamine, or dimethylformamide may be beneficial.

The subsequent addition of a carbon nucleophile to a keto or analdehydic group to obtain a tertiary or secondary alcohol may be carriedout with an alkyl or aryl metal compound, preferably with a lithium ormagnesium derivative. The reactions are preferably conducted in hexanes,ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, benzene, toluene,or mixtures thereof between −80° C. and 50° C.

The subsequent reduction of a keto or an aldehydic group to obtain asecondary or primary alcohol may be carried out with a complex metalhydride such as sodium borohydride, lithium borohydride, lithiumtriethylborohydride, diisobutylaluminum hydide, or lithium aluminumhydride. The reductions may be conducted in e.g. dichloromethane,1,2-dichloroethane, hexanes, ether, dioxane, tetrahydrofuran,dimethylformamide, N-methylpyrrolidinone, benzene, toluene, alcohols,e.g. methanol, water, or mixtures thereof, though, not all reducingagents are compatible with all of these solvents. Preferred temperaturesare between −80° C. and 140° C. depending on the reducing power of thereagent. Alternatively, hydrogen in the presence of a transition metalcatalyst may be used for the reduction.

The subsequent conversion of a cyano into a tetrazolyl group may beachieved by reacting the cyanide with sodium azide or trimethylsilylazide in e.g. toluene, xylene, cyclohexane, dimethylformamide,dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran, dioxane,1,2-dimethoxyethane, alcohol, water, or mixtures thereof. Beneficialadditives may be ZnBr₂, Bu₃SnCl, NH₄Cl, Bu₂SnO, AlCl₃, AlMe₃, HNEt₃Cl,and NEt₃. The reactions are preferably conducted between 20° C. and 160°C.

The subsequent reduction of a nitro group is carried out, for example,with hydrogen and a catalyst such as palladium on carbon, platinumdioxide, or Raney nickel, or using other reducing agents such as iron orzinc in the presence of an acid such as acetic acid.

The subsequent formation of a pyrrolyl ring from an amino group may beaccomplished, for instance, by reacting the amino compound withsuccinaldehyde or a derivative thereof, e.g.2,5-dimethoxy-tetrahydrofuran or hexane-2,5-dione, in the presence of aLewis acid, e.g. acetic acid, p-toluenesulfonic acid, or Bi(OSO₂CF₃)₃,in e.g. acetic acid, water, methanol, ethanol, acetonitrile,1,4-dioxane, tetrahydrofuran, toluene, at 20 to 140° C. Additives suchas molecular sieves or other dehydrating reagents such as aceticanhydride may be beneficial.

In the reactions described hereinbefore, any reactive group present suchas hydroxy, carboxy, amino, alkylamino, or imino group may be protectedduring the reaction by conventional protecting groups which are cleavedagain after the reaction.

For example, a protecting group for a hydroxy group may be atrimethylsilyl, tertbutyldimethylsilyl, triisopropylsilyl, acetyl,pivaloyl, benzoyl, methyl, ethyl, tert-butyl, allyl, trityl, benzyl,4-methoxybenzyl, tetrahydropyranyl, methoxymethyl, ethoxymethyl, or2-trimethylsilylethoxy-methyl group,

-   protecting groups for a carboxy group may be trimethylsilyl, methyl,    ethyl, tertbutyl, allyl, benzyl, or tetrahydropyranyl,-   protecting groups for a ketone or aldehyde may be a ketal or acetal,    respectively, e.g. derived from methanol, glycol, or    propane-1,3-diol, protecting groups for an amino, alkylamino, or    imino group may be methyl, formyl, acetyl, trifluoroacetyl,    ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl,    methoxy-benzyl, or 2,4-dimethoxybenzyl and additionally, for the    amino group, phthalyl, and protecting groups for a terminal alkyne    may be trimethylsilyl, trisopropylsilyl, tertbutyldimethylsilyl, or    2-hydroxy-isopropyl.

Any acyl protecting group may be cleaved, for example, hydrolytically inan aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water,tetrahydrofuran/water, or dioxane/water, in the presence of an acid suchas trifluoroacetic acid, hydrochloric acid, or sulfuric acid or in thepresence of an alkali metal base such as lithium hydroxide, sodiumhydroxide, or potassium hydroxide or aprotically, e.g. in the presenceof iodotrimethylsilane, at temperatures between 0 and 120° C.,preferably between 10 and 100° C. A trifluoroacetyl group is prefer-ablycleaved by treating with an acid such as hydrochloric acid, optionallyin a solvent such as acetic acid, at temperatures between 50 and 120° C.or by treating with sodium hydroxide solution, optionally in anadditional solvent such as tetrahydrofuran or methanol, at temperaturesbetween 0 and 80° C.

Any acetal or ketal protecting group used may be cleaved, for example,hydrolytically in an aqueous solvent, e.g. in water, isopropanol/water,acetic acid/water, tetrahydrofuran/water, or dioxane/water, in thepresence of an acid such as trifluoroacetic acid, hydrochloric acid, orsulfuric acid or aprotically, e.g. in the presence ofiodotrimethylsilane, at temperatures between 0 and 120° C., preferablybetween 10 and 100° C.

A trimethylsilyl group is cleaved, for example, in water, an aqueoussolvent mixture or an alcohol, such as methanol or ethanol, in thepresence of a base such as lithium hydroxide, sodium hydroxide,potassium carbonate, or sodium methoxide.

Acids such as e.g. hydrochloric acid, trifluoroacetic acid, or aceticacid may also be suitable. The cleavage usually takes place atcomparatively low temperatures, e.g. between −60 and 60° C. Silyl groupsother than trimethylsilyl are preferentially cleaved in the presence ofan acid, e.g. trifluoroacetic acid, hydrochloric acid, or sulfuric acid,at temperatures between 0° C. and 100° C. A particularly suited cleavingmethod for silyl groups is based on the use of fluoride salts, e.g.tetrabutylammonium fluoride, hydrogen fluoride, or potassium fluoride,in organic solvents, such as for example diethyl ether, tetrahydrofuran,dioxane, dimethoxyethane, toluene, benzene, dichloroethane, ordichloromethane, at temperatures between −20 and 100° C.

A benzyl, methoxybenzyl, or benzyloxycarbonyl group is advantageouslycleaved hydro-genolytically, e.g. with hydrogen in the presence of acatalyst such as palladium on carbon, palladium hydroxide, or platinumoxide in a solvent such as methanol, ethanol, ethyl acetate, or glacialacetic acid, optionally in the presence of an acid, such as hydrochloricacid, at temperatures between 0 and 100° C., preferably between 20 and60° C., and at hydrogen pressures of 1 to 7 bar, preferably 3 to 5 bar.Trimethylsilyl iodide, boron trichloride, or boron trifluoride in thepresence of a scavenger such as anisol, thioanisol, orpentamethylbenzene may also be used with benzylether derivatives. Anelectron-rich benzyl residue, such as methoxybenzyl, may also be cleavedoxidatively with e.g. 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) orceric ammonium nitrate (CAN) preferably in an alcoholic or aqueoussolvent at temperatures between 10 and 120° C. A 2,4-dimethoxybenzylgroup is preferably cleaved in trifluoroacetic acid in the presence of ascavenger such as anisole.

A tertbutyl or tertbutyloxycarbonyl group is preferably cleaved bytreating with an acid such as trifluoroacetic acid, sulfuric acid, orhydrochloric acid or by treating with iodotrimethylsilane optionallyusing a solvent such as methylene chloride, dioxane, methanol,isopropanol, water, or diethylether.

A methyl group at an tertiary amine may be cleaved by the treatment with1-chloroethyl chloroformate. Hydrobromic acid and borontribromide areparticularly suited for the cleavage of methylethers.

The compounds of general formula I may be resolved into theirenantiomers and/or diastereomers, as mentioned before. Thus, forexample, cis/trans mixtures may be resolved into their cis and transisomers, and racemic compounds may be separated into their enantiomers.

The cis/trans mixtures may be resolved, for example, by chromatographyinto the cis and trans isomers thereof. The compounds of general formulaI which occur as racemates may be separated by methods known per se (cf.Allinger N. L. and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6,Wiley Interscience, 1971) into their optical antipodes anddiastereomeric mixtures of compounds of general formula I may beresolved into their diastereomers by taking advantage of their differentphysico-chemical properties using methods known per se, e.g.chromatography and/or fractional crystallization; if the compoundsobtained thereafter are racemates, they may be resolved into theenantiomers as mentioned above.

The racemates are preferably resolved by column chromatography on chiralphases or by crystallisation from an optically active solvent or byreacting with an optically active sub-stance which forms salts orderivatives, such as e.g. esters or amides, with the racemic compound.Salts may be formed with enantiopure acids for basic compounds and withenantiopure bases for acidic compounds. Diastereomeric derivatives areformed with enantiopure auxiliary compounds such as e.g. acids, theiractivated derivatives, or alcohols. Separation of the diastereomericmixture of salts or derivatives thus obtained may be achieved by takingadvantage of their different physico-chemical properties, e.g.differences in solubility; the free antipodes may be released from thepure diastereomeric salts or derivatives by the action of suitableagents. Optically active acids in common use for such a purpose are e.g.the D- and L-forms of tartaric acid, dibenzoyltartaric acid,di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonicacid, glutamic acid, aspartic acid, or quinic acid. Optically activealcohols applicable as auxiliary may be, for example, (+) or (−)-mentholand optically active acyl groups in amides may be, for example, (+)- or(−)-menthyloxycarbonyl.

As mentioned above, the compounds of formula I may be converted intosalts, particularly for pharmaceutical use into the physiologicallyacceptable salts with inorganic or organic acids provided that compoundI bears a basic residue. Acids which may be used for this purposeinclude for example hydrochloric acid, hydrobromic acid, sulfuric acid,methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid,lactic acid, citric acid, tartaric acid, or maleic acid.

If the compounds of formula I contain an acidic residue like, forexample, a carboxy group, they may be converted into the salts thereofwith inorganic or organic bases, particularly for pharmaceutical useinto the physiologically acceptable salts thereof. Suitable bases forthis purpose include, for example, sodium hydroxide, potassiumhydroxide, calcium hydroxide, calcium isopropoxide, magnesium hydroxide,magnesium ethoxide, ammonium hydroxide, cyclohexylamine, ethanolamine,diethanolamine, triethanolamine, N-methyl-D-glucamine, L-lysine,L-arginine, and piperazine.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise stated, the groups, residues and substituents,particularly R¹ to R¹⁴, L, X, m, n, and o are defined as above andhereinafter. If residues, substituents, or groups occur several times ina compound they may have the same or different meanings. Some preferredmeanings of individual scaffolds, groups, and substituents of thecompounds according to the invention will be given hereinafter.

First Aspect of the Invention

A first subgeneric embodiment of this invention is directed to compoundsdescribed by general formula I.1

wherein the bicyclic core structure of general formula I.1 is optionallysubstituted with R¹¹ to R¹⁴, and

-   wherein R¹ to R³ and R¹¹ to R¹⁴ are defined as hereinbefore and    hereinafter, except for the compounds comprised by the formulae II.1    to II.8, their tautomers, their stereoisomers, mixtures thereof and    the salts thereof.

A second subgeneric embodiment of this invention is directed tocompounds described by general formula I.2

wherein the bicyclic core structure of general formula I.2 is optionallysubstituted with R¹¹ to R¹⁴, and

-   wherein R¹ to R³ and R¹¹ to R¹⁴ are defined as hereinbefore and    hereinafter, their tautomers, their stereoisomers, mixtures thereof    and the salts thereof.

A third subgeneric embodiment of this invention is directed to compoundsdescribed by general formula I.3

wherein the bicyclic core structure of general formula I.3 is optionallysubstituted with R¹¹ to R¹⁴, and

-   wherein R¹ to R³ and R¹¹ to R¹⁴ are defined as hereinbefore and    hereinafter, their tautomers, their stereoisomers, mixtures thereof    and the salts thereof.

A fourth subgeneric embodiment of this invention is directed tocompounds described by general formula I.4

wherein the bicyclic core structure of general formula I.4 is optionallysubstituted with R¹¹ to R¹⁴, and

-   wherein R¹ to R³ and R¹ to R¹⁴ are defined as hereinbefore and    hereinafter, their tautomers, their stereoisomers, mixtures thereof    and the salts thereof.

A fifth subgeneric embodiment of this invention is directed to compoundsdescribed by general formula I.5

wherein the bicyclic core structure of general formula I.5 is optionallysubstituted with R¹¹ to R¹⁴, and

-   wherein R¹ to R³ and R¹¹ to R¹⁴ are defined as hereinbefore and    hereinafter, while the compounds of formulae II.7 and II.8 are    excluded,-   their tautomers, their stereoisomers, mixtures thereof and the salts    thereof.

A sixth subgeneric embodiment of this invention is directed to compoundsdescribed by general formula I.6

wherein the bicyclic core structure of general formula I.6 is optionallysubstituted with R¹¹ to R¹⁴, and

-   wherein R¹ to R³ and R¹¹ to R¹⁴ are defined as hereinbefore and    hereinafter, their tautomers, their stereoisomers, mixtures thereof    and the salts thereof.

A seventh subgeneric embodiment of this invention is directed tocompounds described by general formula I.7

wherein the bicyclic core structure of general formula I.7 is optionallysubstituted with R¹¹ to R¹⁴, and

-   wherein R¹ to R³ and R¹¹ to R¹⁴ are defined as hereinbefore and    hereinafter, while the compounds comprised by the formula II.3 are    excluded,-   their tautomers, their stereoisomers, mixtures thereof and the salts    thereof.

An eighth subgeneric embodiment of this invention is directed tocompounds described by general formula I.8

wherein the bicyclic core structure of general formula I.8 is optionallysubstituted with R¹¹ to R¹⁴, and

-   wherein R¹ to R³ and R¹¹ to R¹⁴ are defined as hereinbefore and    hereinafter, their tautomers, their stereoisomers, mixtures thereof    and the salts thereof.

A ninth subgeneric embodiment of this invention is directed to compoundsdescribed by general formula I.9

wherein the bicyclic core structure of general formula I.9 is optionallysubstituted with R¹¹ to R¹⁴, and

-   wherein R¹ to R³ and R¹¹ to R¹⁴ are defined as hereinbefore and    hereinafter, their tautomers, their stereoisomers, mixtures thereof    and the salts thereof.

A tenth subgeneric embodiment of this invention is directed to compoundsdescribed by general formula I.10

wherein the bicyclic core structure of general formula I.10 isoptionally substituted with R¹¹ to R¹⁴, and

-   wherein R¹ to R³ and R¹¹ to R¹⁴ are defined as hereinbefore and    hereinafter, their tautomers, their stereoisomers, mixtures thereof    and the salts thereof.

Preferred compounds according to the invention are those of generalformulae I.1 to I.10, wherein

-   R¹ denotes aryl or heteroaryl,    -   while by aryl is meant phenyl or naphthyl and    -   by heteroaryl is meant pyrrolyl, furanyl, thienyl, pyridinyl,        indolyl, benzofuranyl, benzo-thiophenyl, quinolinyl,        isoquinolinyl, or    -   pyrrolyl, furanyl, thienyl, pyridinyl wherein 1 or 2 CH are        replaced by N, or    -   indolyl, benzofuranyl, benzothiophenyl, quinolinyl,        isoquinolinyl, wherein 1 or 2 CH are replaced by N, or    -   1-oxo-indanyl, 2,3-dihydro-indolyl, 2,3-dihydro-2-oxo-indolyl,        2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxo-1H-benzimidazolyl,        2,3-dihydro-2-oxo-benzoxazolyl, benzo[1,3]-dioxolyl,        1,2-dihydro-2-oxo-quinolinyl, 1,4-dihydro-4-oxo-quinolinyl,        1,2-dihydro-1-oxo-isoquinolinyl, 1,2-dihydro-2-oxo-quinazolinyl,        1,4-dihydro-4-oxo-quinazolinyl, 1,2-dihydro-2-oxoquinoxalinyl,        or 1,2,3,4-tetrahydro-3-oxo-quinoxalinyl,    -   wherein the above-mentioned aryl and heteroaryl rings are        optionally independently substituted with one R⁴, one to four        identical or different R⁵, and one R⁶.

Preferably R¹ denotes phenyl, naphthyl, furanyl, pyrazolyl, imidazolyl,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzimidazolyl,indazolyl, benzotriazolyl, benzoxazolyl, benzo-thiazolyl, quinolinyl,isoquinolinyl, quinazolinyl, naphthyridinyl, quinoxalinyl,2,3-dihydro-2-oxo-indolyl, or 1,2,3,4-tetrahydro-3-oxo-quinoxalinyl,wherein any of these groups optionally are independently substitutedwith one R⁴, one to four identical or different R⁵, and one R⁶.

More preferably, R¹ denotes phenyl, naphthyl, pyrazolyl, pyridinyl,pyrimidinyl, naphthyl, benzofuranyl, indolyl, benzothiophenyl,benzimidazolyl, indazolyl, benzotriazolyl, benzoxazolyl, benzothiazolyl,quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl, quinoxalinyl,2,3-dihydro-2-oxo-indolyl, or 1,2,3,4-tetrahydro-3-oxo-quinoxalinyl,wherein any of these groups optionally are independently substitutedwith one R⁴ and one to four different or identical R⁵.

Most preferably, R¹ denotes phenyl, pyrazolyl, pyridinyl, benzofuranyl,indolyl, benzimidazolyl, indazolyl, benzotriazolyl, benzothiazolyl,2,3-dihydro-2-oxo-indolyl, or 1,2,3,4-tetrahydro-3-oxo-quinoxalinyl,wherein any of these groups optionally are independently substitutedwith one R⁴ and one to four different or identical R⁵.

Particularly preferred are 4-carbamoyl-phenyl,4-(morpholin-4-ylmethyl)phenyl, 4-amino-phenyl, 4-hydroxyphenyl,4-amino-3-fluoro-phenyl, 4-amino-3-chloro-phenyl,4-amino-3,5-dichloro-phenyl, indol-3-yl, indol-5-yl, indol-6-yl,benzimidazol-5-yl, indazol-5-yl, benzothiazol-5-yl, andbenzothiazol-6-yl.

R² and R³, together with the double bond to which they are attached,denote a benzo or pyrido ring, optionally both independently substitutedwith R⁷, R⁸ and R⁹, or denote a furo, pyrrolo, pyridazino, pyrimido, orpyrazino ring, wherein any of these groups optionally are independentlysubstituted with R⁷ and R⁸ or R⁸ and R⁹, or denote a pyrazolo, imidazo,oxazolo, thiazolo, isoxazolo, or isothiazolo ring, wherein any of thesegroups optionally are independently substituted with R⁷.

Preferably, R² and R³, together with the double bond to which they areattached, denote a benzo or pyrido ring, both optionally independentlysubstituted with R⁷, R⁸ and R⁹, or denote a pyrrolo, pyridazino,pyrimido, or pyrazino ring, wherein any of these groups optionally areindependently substituted with R⁷ and R⁸ or R⁸ and R⁹, or denote apyrazolo or imidazo ring, both optionally substituted with R⁷.

More preferably, R² and R³, together with the double bond to which theyare attached, denote a benzo or pyrido ring, both independentlysubstituted with R⁷, R⁸ and R⁹, or denote a pyrrolo ring optionallysubstituted independently with R⁷ and R⁸ or R⁸ and R⁹, particularly abenzo ring optionally substituted independently with R⁷, R⁸ and R⁹.

R⁴ denotes fluorine, chlorine, bromine, C₁₋₄-alkyl, hydroxy,C₁₋₄-alkyloxy,

-   -   nitro, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino,        pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl, piperidin-1-yl,        2-oxo-piperidin-1-yl, morpholin-4-yl, 3-oxo-morpholin-4-yl,        piperazin-1-yl, 2-oxo-piperazin-1-yl, 3-oxo-piperazin-1-yl,        4-(C₁₋₃-alkyl)-piperazin-1-yl,        4-(C₁₋₄-alkylcarbonyl)-piperazin-1-yl,        4-(C₃₋₆-cycloalkylcarbonyl)-piperazin-1-yl,        4-(C₁₋₄-alkyloxycarbonyl)-piperazin-1-yl,        4-(C₁₋₄-alkylsulfonyl)-piperazin-1-yl,        2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,        3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,    -   C₁₋₃-alkyl-carbonylamino, (het)arylcarbonylamino,        (het)aryl-C₁₋₃-alkyl-carbonylamino, C₁₋₃-alkyloxy-carbonylamino,        aminocarbonylamino, C₁₋₃-alkyl-aminocarbonylamino,        di-(C₁₋₃-alkyl)aminocarbonylamino,        pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonyl-amino,        morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino,        4-(C₁₋₃-alkyl)-pi-perazin-1-yl-carbonylamino,        C₁₋₃-alkyl-sulfonylamino, (het)arylsulfonylamino,        (het)aryl-C₁₋₃-alkyl-sulfonylamino,    -   N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-carbonylamino,        N—(C₁₋₃-alkyl)-(het)arylcarbonylamino,        N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkyl-carbonylamino,        N—(C₁₋₃-alkyl)-C₁₋₃-alkyloxy-carbonylamino,        N-(aminocarbonyl)-C₁₋₃-alkylamino,        N—(C₁₋₃-alkyl-aminocarbonyl)-C₁₋₃-alkylamino,        N-[di-(C₁₋₃-alkyl)aminocarbonyl]-C₁₋₃-alkylamino,        N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-sulfonylamino,        N—(C₁₋₃-alkyl)-(het)arylsulfonylamino,        N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkyl-sulfonylamino,    -   oxo-imidazolidin-1-yl, 2,4-dioxo-imidazolidin-1-yl,        2,5-dioxo-imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl,        wherein the nitrogen atom in position 3 of the aforementioned        groups is optionally substituted with methyl,    -   cyano, carboxy, C₁₋₃-alkyloxy-carbonyl, aminocarbonyl,        C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,        pyrrolidin-1-yl-carbonyl,        2-(methoxymethyl)-pyrrolidin-1-yl-car-bonyl,        3-(methoxymethyl)-pyrrolidin-1-yl-carbonyl,        piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl,        piperazin-1-yl-carbonyl, 4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl,        (het)arylaminocarbonyl, N—(C₁₋₃-alkyl)-(het)arylaminocarbonyl,        (het)aryl-C₁₋₃-alkylaminocarbonyl,        N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkylaminocarbonyl,    -   C₁₋₃-alkyl-carbonyl, (het)aryl-carbonyl,    -   carboxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyl,        cyano-C₁₋₃-alkyl, aminocarbonyl-C₁₋₃-alkyl,        C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyl,        di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl,        pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl,        piperidin-1-yl-carbonyl-C₁₋₃-alkyl,        morpholin-4-yl-carbonyl-C₁₋₃-alkyl,        piperazin-1-yl-carbonyl-C₁₋₃-alkyl,        4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl-C₁₋₃-alkyl,    -   carboxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyloxy,        cyano-C₁₋₃-alkyloxy, amino-carbonyl-C₁₋₃-alkyloxy,        C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyloxy,        di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyloxy,        pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl-oxy,        piperidin-1-yl-carbonyl-C₁₋₃-alkyloxy,        morpholin-4-yl-carbonyl-C₁₋₃-alkyl-oxy,        piperazin-1-yl-carbonyl-C₁₋₃-alkyloxy,        4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl-C₁₋₃-alkyloxy,    -   hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-C₁₋₃-alkyl, amino-C₁₋₃-alkyl,        C₁₋₃-alkylamino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,        pyrrolidin-1-yl-C₁₋₃-alkyl, 2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyl,        piperidin-1-yl-C₁₋₃-alkyl, 2-oxo-piperidin-1-yl-C₁₋₃-alkyl,        morpholin-4-yl-C₁₋₃-alkyl, (methyl-morpholin-4-yl)-C₁₋₃-alkyl,        (dimethyl-morpholin-4-yl)-C₁₋₃-alkyl,        3-oxo-morpholin-4-yl-C₁₋₃-alkyl, piperazin-1-yl-C₁₋₃-alkyl,        2-oxo-piperazin-1-yl-C₁₋₃-alkyl,        3-oxo-piperazin-1-yl-C₁₋₃-alkyl,        4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyl,        2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyl,        3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyl,    -   C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl,        (het)arylcarbonylamino-C₁₋₃-alkyl,    -   hydroxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-C₁₋₃-alkyloxy,        C₁₋₃-alkylsulfanyl-C₁₋₃-alkyloxy,        C₁₋₃-alkylsulfinyl-C₁₋₃-alkyloxy,        C₁₋₃-alkylsulfonyl-C₁₋₃-alkyloxy, amino-C₁₋₃-alkyloxy,        C₁₋₃-alkylamino-C₁₋₃-alkyloxy,        di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyloxy,        pyrrolidin-1-yl-C₁₋₃-alkyloxy,        2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyloxy,        piperidin-1-yl-C₁₋₃-alkyloxy,        2-oxo-piperidin-1-yl-C₁₋₃-alkyloxy,        morpholin-4-yl-C₁₋₃-alkyloxy,        3-oxo-morpholin-4-yl-C₁₋₃-alkyloxy,        piperazin-1-yl-C₁₋₃-alkyloxy,        2-oxo-piperazin-1-yl-C₁₋₃-alkyloxy,        3-oxo-piperazin-1-yl-C₁₋₃-alkyloxy,        4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyloxy,        2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyloxy,        3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyloxy,    -   C_(1,3)-alkylsulfanyl, C₁₋₃-alkysulfinyl, C₁₋₃-alkylsulfonyl,        (het)arylsulfonyl,    -   aminosulfonyl, C₁₋₃-alkyl-aminosulfonyl,        di-(C₁₋₃-alkyl)-aminosulfonyl, pyrrolidin-1-yl-sulfonyl,        piperidin-1-yl-sulfonyl, morpholin-4-yl-sulfonyl,        piperazin-1-yl-sulfonyl, 4-(C₁₋₃-alkyl)-piperazin-1-yl-sulfonyl,    -   difluoromethyl, trifluoromethyl, difluoromethoxy,        trifluoromethoxy,2,2,2-trifluoro-1-hydroxyethyl,        2,2,2-trifluoro-1-hydroxy-1-methylethyl,        2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl,    -   C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyloxy, C₃₋₆-cycloalkyl-C₁₋₃-alkyl,        C₃₋₆-cycloalkyl-C₁₋₃-alkyl-oxy,    -   (het)aryl, (het)aryloxy, (het)aryl-C₁₋₃-alkyl,        (het)aryl-C₁₋₃-alkyloxy, (het)aryloxy-C₁₋₃-alkyl, or    -   tetrahydrofuran-3-yl-oxy, tetrahydropyran-3-yl-oxy,        tetrahydropyran-4-yl-oxy, tetra-hydrofuranyl-C₁₋₃-alkyloxy,        tetrahydropyranyl-C₁₋₃-alkyloxy,    -   wherein the above-mentioned (het)aryl groups are phenyl,        naphthyl, or    -   pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl,        benzothiophenyl, quinolinyl, isoquinolinyl, or    -   pyrrolyl, furanyl, thienyl, pyridyl wherein 1 or 2 CH are        replaced by N, or    -   indolyl, benzofuranyl, benzothiophenyl, quinolinyl,        isoquinolinyl wherein 1 to 3 CH are replaced by N, or    -   1,2-dihydro-2-oxo-pyridinyl, 1,4-dihydro-4-oxo-pyridinyl,        2,3-dihydro-3-oxo-pyridazinyl,        1,2,3,6-tetrahydro-3,6-dioxo-pyridazinyl,        1,2-dihydro-2-oxo-pyrimidinyl, 3,4-dihydro-4-oxo-pyrimidinyl,        1,2,3,4-tetrahydro-2,4-dioxo-pyrimidinyl,        1,2-dihydro-2-oxo-pyrazinyl,        1,2,3,4-tetrahydro-2,3-dioxo-pyrazinyl,        2,3-dihydro-2-oxo-indolyl, 2,3-dihydrobenzo-furanyl,        2,3-dihydro-2-oxo-1H-benzimidazolyl,        2,3-dihydro-2-oxo-benzoxazolyl, 1,2-dihydro-2-oxo-quinolinyl,        1,4-dihydro-4-oxo-quinolinyl, 1,2-dihydro-1-oxo-isoquinolinyl,        1,4-dihydro-4-oxo-cinnolinyl, 1,2-dihydro-2-oxo-quinazolinyl,        1,4-dihydro-4-oxo-quina-zolinyl,        1,2,3,4-tetrahydro-2,4-dioxo-quinazolinyl,        1,2-dihydro-2-oxoquinoxalinyl,        1,2,3,4-tetrahydro-3-oxo-quinoxalinyl,        1,2,3,4-tetrahydro-2,3-dioxo-quinoxalinyl,        1,2-dihydro-1-oxo-phthalazinyl,        1,2,3,4-tetrahydro-1,4-dioxo-phthalazinyl, chromanyl,        coumarinyl, 2,3-dihydro-benzo[1,4]dioxinyl, or        3,4-dihydro-3-oxo-2H-benzo[1,4]oxazin-yl, and    -   wherein any of the groups mentioned for the (het)aryl groups are        optionally substituted with one or two R¹⁰ which may be        identical or different.

Preferably R⁴ denotes fluorine, chlorine, bromine, C₁₋₄-alkyl, hydroxy,C₁₋₄-alkyloxy,

-   -   amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino, pyrrolidin-1-yl,        2-oxo-pyrrolidin-1-yl, piperidin-1-yl, 2-oxo-piperidin-1-yl,        morpholin-4-yl, 3-oxo-morpholin-4-yl, piperazin-1-yl,        2-oxo-piperazin-1-yl, 3-oxo-piperazin-1-yl,        4-(C₁₋₃-alkyl)-piperazin-1-yl,        4-(C₁₋₄-alkyl-carbonyl)-piperazin-1-yl,        4-(C₃₋₆-cycloalkylcarbonyl)-piperazin-1-yl,        4-(C₁₋₄-alkyloxy-carbonyl)-piperazin-1-yl,        4-(C₁₋₄-alkylsulfonyl)-piperazin-1-yl,        2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,        3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,    -   C₁₋₃-alkyl-carbonylamino, (het)arylcarbonylamino,        (het)aryl-C₁₋₃-alkyl-carbonylamino, C₁₋₃-alkyloxy-carbonylamino,        aminocarbonylamino, C₁₋₃-alkyl-aminocarbonylamino,        di-(C₁₋₃-alkyl)aminocarbonylamino,        pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonyl-amino,        morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino,        4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonylamino,    -   cyano, carboxy, C₁₋₃-alkyloxy-carbonyl, aminocarbonyl,        C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,        pyrrolidin-1-yl-carbonyl,        2-(methoxymethyl)-pyrrolidin-1-yl-carbonyl,        3-(methoxymethyl)-pyrrolidin-1-yl-carbonyl,        piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl,        piperazin-1-yl-carbonyl, 4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl,        N—(C₁₋₃-alkyl)-(het)arylaminocarbonyl,        N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkylaminocarbonyl,    -   C₁₋₃-alkyl-carbonyl, (het)aryl-carbonyl,    -   hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-C₁₋₃-alkyl, amino-C₁₋₃-alkyl,        C₁₋₃-alkylamino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,        pyrrolidin-1-yl-C₁₋₃-alkyl, 2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyl,        morpholin-4-yl-C₁₋₃-alkyl, (methyl-morpholin-4-yl)-C₁₋₃-alkyl,        (dimethyl-morpholin-4-yl)-C₁₋₃-alkyl,        3-oxo-morpholin-4-yl-C₁₋₃-alkyl,    -   C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl,        (het)arylcarbonylamino-C₁₋₃-alkyl,    -   hydroxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-C₁₋₃-alkyloxy,    -   trifluoromethyl, difluoromethoxy, trifluoromethoxy,        2,2,2-trifluoro-1-hydroxyethyl,        2,2,2-trifluoro-1-hydroxy-1-methylethyl,        2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl,        aminosulfonyl,    -   (het)aryl, (het)aryl-C₁₋₃-alkyl, or (het)aryloxy,    -   wherein the above-mentioned (het)aryl groups are phenyl,        naphthyl, pyrrolyl, furanyl, thienyl, pyridyl, indolyl,        benzofuranyl, benzothiophenyl, quinolinyl, and isoquinolinyl, or    -   pyrrolyl, furanyl, thienyl, or pyridyl wherein 1 or 2 CH are        replaced by N, or    -   indolyl, benzofuranyl, benzothiophenyl, quinolinyl, or        isoquinolinyl wherein 1 to 3 CH are replaced by N, and    -   wherein the above-mentioned (het)aryl groups optionally are        substituted with R¹⁰.

-   More preferably, R⁴ denotes fluorine, chlorine, C₁₋₄-alkyl, hydroxy,    C₁₋₄-alkyloxy, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino,    pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl,    C₁₋₃-alkyl-carbonylamino, aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl,    di-(C₁₋₃-alkyl)-aminocarbonyl, (N-methyl)-benzylaminocarbonyl,    (N-methyl)-phenylaminocarbonyl, pyrrolidin-1-yl-carbonyl,    2-(methoxymethyl)-pyrrolidin-1-yl-carbonyl,    3-(methoxymethyl)-pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl,    morpholin-4-yl-carbonyl, hydroxy-C₁₋₃-alkyl,    C₁₋₃-alkyloxy-C₁₋₃-alkyl, amino-C₁₋₃-alkyl,    C₁₋₃-alkylamino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,    morpholin-4-yl-C₁₋₃-alkyl, (2-methyl-morpholin-4-yl)-C₁₋₃-alkyl,    (2,6-dimethyl-morpholin-4-yl)-C₁₋₃-alkyl,    3-oxo-morpholin-4-yl-methyl, pyrrolidin-1-yl-C₁₋₃-alkyl,    2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyl,    C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl, phenylcarbonylamino-C₁₋₃-alkyl,    imidazolyl-C₁₋₃-alkyl, triazolyl-C₁₋₃-alkyl, trifluoromethyl,    difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoro-1-hydroxyethyl,    2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, or    2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, or aminosulfonyl.

-   Most preferably, R⁴ denotes fluorine, chlorine, methyl, hydroxy,    methoxy, methylamino, morpholin-4-yl, acetylamino, aminocarbonyl,    (N-methyl)-propylaminocarbonyl, (N-methyl)-benzylaminocarbonyl,    (N-methyl)-phenylaminocarbonyl, dimethylamino-carbonyl,    diethylaminocarbonyl, piperidin-1-ylcarbonyl,    morpholin-4-ylcarbonyl, pyrrolidin-1-yl-carbonyl,    2-(methoxymethyl)-pyrrolidin-1-yl-carbonyl, 1-hydroxy-ethyl,    1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl,    2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl,    acetylaminomethyl, phenylcarbonylaminomethyl,    2-oxo-pyrrolidin-1-yl-methyl, morpholin-4-yl-methyl,    3-oxo-morpholin-4-yl-methyl, imidazol-1-ylmethyl,    triazol-1-ylmethyl, (2-methylmorpholin-4-yl)-methyl, or    aminosulfonyl.

R⁵ and R⁶ are independently selected from among fluorine, chlorine,bromine, C₁₋₃-alkyl, C₂₋₃-alkynyl, trifluoromethyl, hydroxy,C₁₋₃-alkyloxy, and cyano, preferably from hydrogen, fluorine, chlorine,methyl, ethyl, ethynyl, trifluoromethyl, hydroxy, methoxy, and ethoxy,more preferably from hydrogen, fluorine, chlorine, methyl, ethynyl,hydroxy, and methoxy.

If R⁵ and R⁶ are bound to adjacent carbon atoms they together mayadditionally denote methylenedioxy, difluoromethylenedioxy,ethylenedioxy, or C₃₋₅-alkylene, preferably methylenedioxy,ethylene-1,2-dioxy, propylene, or butylene, more preferablymethylenedioxy or ethylene-1,2-dioxy, most preferablyethylene-1,2-dioxy.

Preferably R⁷ denotes fluorine, chlorine, C₁₋₄-alkyl, hydroxy,C₁₋₄-alkyloxy,

-   -   nitro, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino,        pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl, piperidin-1-yl,        2-oxo-piperidin-1-yl, morpholin-4-yl, 3-oxo-morpholin-4-yl,        3-oxo-piperazin-1-yl, 4-(C₁₋₄-alkylcarbonyl)-piperazin-1-yl,    -   C₁₋₃-alkyl-carbonylamino, (het)aryl-carbonylamino,        C₁₋₃-alkyloxy-carbonylamino, C₁₋₃-alkyl-aminocarbonylamino,        di-(C₁₋₃-alkyl)aminocarbonylamino,        pyrrolidin-1-yl-carbonyl-amino, piperidin-1-yl-carbonylamino,        morpholin-4-yl-carbonylamino, C₁₋₃-alkyl-sulfonyl-amino,        C₁₋₃-alkylamino-sulfonylamino,        di-(C₁₋₃-alkyl)amino-sulfonylamino,        pyrrolidin-1-yl-sulfonylamino, piperidin-1-yl-sulfonylamino,        morpholin-4-yl-sulfonylamino, (het)aryl-sulfonylamino,    -   N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-carbonylamino,        N—(C₁₋₃-alkyl)-(het)arylcarbonylamino,        N—(C₁₋₃-alkyl)-C₁₋₃-alkyloxy-carbonylamino,        N—(C₁₋₃-alkyl-aminocarbonyl)-C₁₋₃-alkylamino,        N-[di-(C₁₋₃-alkyl)aminocarbonyl]-C₁₋₃-alkylamino,        N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-sulfonylamino,        N—(C₁₋₃-alkyl)-(het)arylsulfonylamino,    -   cyano, (hydroxyimino)aminomethyl,        (C₁₋₃-alkyloxyimino)aminomethyl, carboxy,        C₁₋₃-alkyloxy-carbonyl, aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl,        di-(C₁₋₃-alkyl)-amino-carbonyl, pyrrolidin-1-yl-carbonyl,        piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl,    -   C₁₋₃-alkyl-carbonyl, (het)aryl-carbonyl,    -   carboxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyl,        cyano-C₁₋₃-alkyl, aminocarbonyl-C₁₋₃-alkyl,        C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyl,        di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl,        pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl,        piperidin-1-yl-carbonyl-C₁₋₃-alkyl,        morpholin-4-yl-carbonyl-C₁₋₃-alkyl,    -   carboxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyloxy,        cyano-C₁₋₃-alkyloxy, aminocarbonyl-C₁₋₃-alkyloxy,        C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyloxy,        di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyloxy,        pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl-oxy,        piperidin-1-yl-carbonyl-C₁₋₃-alkyloxy,        morpholin-4-yl-carbonyl-C₁₋₃-alkyl-oxy,    -   hydroxy-C₁₋₄-alkyl, C₁₋₃-alkyloxy-C₁₋₄-alkyl, amino-C₁₋₃-alkyl,        C₁₋₃-alkylamino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,        pyrrolidin-1-yl-C₁₋₃-alkyl, 2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyl,        C₁₋₄-alkylcarbonyl-amino-C₁₋₃-alkyl,        N—(C₁₋₃-alkyl)-C₁₋₄-alkylcarbonyl-amino-C₁₋₃-alkyl,        2-oxo-piperidin-1-yl-C₁₋₃-alkyl,        3-oxo-morpholin-4-yl-C₁₋₃-alkyl,    -   hydroxy-C₁₋₄-alkyloxy, C₁₋₄-alkyloxy-C₁₋₄-alkyloxy,        C₁₋₃-alkylsulfinyl-C₁₋₃-alkyloxy,        C₁₋₃-alkylsulfonyl-C₁₋₃-alkyloxy,        di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyloxy,        2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyloxy,        2-oxo-piperidin-1-yl-C₁₋₃-alkyloxy,        morpholin-4-yl-C₁₋₃-alkyloxy,        3-oxo-morpholin-4-yl-C₁₋₃-alkyloxy,    -   C₁₋₄-alkylsulfanyl, C₁₋₄-alkysulfinyl, C₁₋₄-alkylsulfonyl,        (het)arylsulfonyl, C₃₋₆-cycloalkylsulfanyl,        C₃₋₆-cycloalkylsulfinyl, C₃₋₆-cycloalkylsulfonyl,    -   aminosulfonyl, C₁₋₃-alkyl-aminosulfonyl,        di-(C₁₋₃-alkyl)-aminosulfonyl, pyrrolidin-1-yl-sulfonyl,        piperidin-1-yl-sulfonyl, morpholin-4-yl-sulfonyl,    -   difluoromethyl, trifluoromethyl, difluoromethoxy,        trifluoromethoxy,    -   C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyloxy, C₃₋₆-cycloalkyl-C₁₋₃-alkyl,        C₃₋₆-cycloalkyl-C₁₋₃-alkoxy,    -   (het)aryl, (het)aryloxy, (het)aryl-C₁₋₃-alkyl,        (het)aryl-C₁₋₃-alkyloxy, (het)aryloxy-C₁₋₃-alkyl, or    -   tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,        tetrahydropyran-4-yloxy, tetrahydro-furanyl-C₁₋₃-alkyloxy, or        tetrahydropyranyl-C₁₋₃-alkyloxy,        wherein the above-mentioned (het)aryl groups are defined as        described hereinbefore under R⁴.

More preferably R⁷ denotes fluorine, chlorine, C₁₋₄-alkyl, hydroxy,C₁₋₄-alkyloxy,

-   -   nitro, amino, C₁₋₃-alkylamino,    -   2-oxo-pyrrolidin-1-yl, 2-oxo-piperidin-1-yl, morpholin-4-yl,        3-oxo-morpholin-4-yl,    -   C₁₋₃-alkyl-carbonylamino, (het)aryl-carbonylamino,        C₁₋₃-alkyl-sulfonylamino,        N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-carbonylamino,        N—(C₁₋₃-alkyl)-(het)arylcarbonylamino,        N—(C₁₋₁₃-alkyl)-C₁₋₃-alkyl-sulfonylamino,        N—(C₁₋₃-alkyl)-(het)arylsulfonylamino, cyano,        (hydroxyimino)aminomethyl, (C₁₋₃-alkyloxyimino)aminomethyl,        carboxy, C₁₋₃-alkyloxy-carbonyl, aminocarbonyl,        C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,        pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl,        morpholin-4-yl-carbonyl, C₁₋₃-alkyl-carbonyl,    -   carboxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyl,        cyano-C₁₋₃-alkyl, aminocarbonyl-C₁₋₃-alkyl,        C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyl,        di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl,        pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl,        piperidin-1-yl-carbonyl-C₁₋₃-alkyl,        morpholin-4-yl-carbonyl-C₁₋₃-alkyl,    -   cyano-C₁₋₃-alkyloxy, aminocarbonyl-C₁₋₃-alkyloxy,        C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyl-oxy,        di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyloxy,        pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl-oxy,        piperidin-1-yl-carbonyl-C₁₋₃-alkyloxy,        morpholin-4-yl-carbonyl-C₁₋₃-alkyl-oxy,    -   hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-C₁₋₃-alkyl,        C₁₋₄-alkylcarbonyl-amino-C₁₋₃-alkyl,        N—(C₁₋₃-alkyl)-C₁₋₄-alkylcarbonyl-amino-C₁₋₃-alkyl,        2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyl,        2-oxo-piperid-in-1-yl-C₁₋₃-alkyl,        3-oxo-morpholin-4-yl-C₁₋₃-alkyl, hydroxy-C₁₋₃-alkyloxy,        C₁₋₃-alkyloxy-C₁₋₃-alkyloxy,    -   C₁₋₄-alkylsulfanyl, C₁₋₄-alkysulfinyl, C₁₋₄-alkylsulfonyl,        C₃₋₆-cycloalkylsulfanyl, C₃₋₆-cycloalkylsulfinyl,        C₃₋₆-cycloalkylsulfonyl,    -   aminosulfonyl, C_(1,3)-alkyl-aminosulfonyl,        di-(C₁₋₃-alkyl)-aminosulfonyl,    -   trifluoromethyl, difluoromethoxy, trifluoromethoxy,    -   C₃₋₆-cycloalkyloxy, tetrahydrofuran-3-yloxy,        tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy,        tetrahydrofuranyl-C₁₋₃-alkyloxy,        tetrahydropyranyl-C₁₋₃-alkyloxy,    -   (het)aryl or (het)aryloxy,        wherein the above-mentioned (het)aryl groups for R⁷ denote        phenyl, furanyl, thienyl, oxazolyl, thiazolyl, isoxazolyl,        imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl,        pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl,        wherein any of these groups are optionally mono- or        disubstituted with R¹⁰. Most preferably R⁷ denotes fluorine,        chlorine, C₁₋₃-alkyl, hydroxy, C₁₋₃-alkyloxy, amino,        C₁₋₃-alkyl-carbonylamino, C₁₋₃-alkyl-sulfonylamino, cyano,        (hydroxyimino)aminomethyl, carboxy, C₁₋₃-alkyloxy-carbonyl,        aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl,        di-(C₁₋₃-alkyl)-aminocarbonyl, hydroxy-C₁₋₃-alkyl,        trifluoromethyl-hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-C₁₋₃-alkyl,        C₁₋₃-alkyl-carbonyl-amino-C₁₋₃-alkyl, hydroxy-C₁₋₃-alkyloxy,        C₁₋₃-alkyloxy-C₁₋₃-alkyloxy, trifluoromethyl, difluoromethoxy,        trifluoromethoxy, C₁₋₃-alkylcarbonyl, C₁₋₄-alkylsulfonyl,        C₃₋₆-cycloalkylsulfonyl,

-   aminosulfonyl, C₁₋₃-alkyl-aminosulfonyl,    di-(C₁₋₃-alkyl)-aminosulfonyl, or

-   a (het)aryl group selected from phenyl, pyrrol-1-yl,    4-methyl-4H-[1,2,4]triazol-3-yl, oxadiazolyl, pyridinyl,    1,2-dihydro-1-methyl-2-oxo-pyridinyl, pyrimidinyl, pyridazinyl, and    2,3-dihydro-2-methyl-3-oxo-pyridazinyl, each of them being    optionally monosubstituted with R¹⁰;

-   particularly R⁷ denotes fluorine, chlorine, methyl, hydroxy,    methoxy, amino, acetylamino, methylsulfonylamino, cyano,    (hydroxyimino)aminomethyl, carboxy, methoxycarbonyl, ethoxycarbonyl,    aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl,    acetylaminomethyl, acetyl, 1-hydroxy-ethyl,    1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl,    methylsulfonyl, aminosulfonyl, methylaminosulfonyl,    dimethylaminosulfonyl, phenyl, pyrrol-1-yl, pyridin-3-yl,    pyridin-4-yl, 1,2-dihydro-1-methyl-2-oxo-pyridin-5-yl,    1,2-dihydro-1-methyl-2-oxo-pyridin-4-yl, pyrimidin-4-yl,    2-methyl-pyrimidin-4-yl, 2-methyl-pyrimidin-5-yl,    6-methyl-pyridazin-3-yl, 2,3-dihydro-2-methyl-3-oxo-pyridazin-6-yl,    4,5-dimethyl-4H-[1,2,4]triazol-3-yl, oxadiazolyl, or    methyloxadiazolyl.

R⁸ and R⁹, which may be identical or different, denote fluorine,chlorine, bromine, C₁₋₃-alkyl, trifluoromethyl, hydroxy, C₁₋₃-alkyloxy,or cyano. More preferably R⁸ and R⁹ independently denote fluorine,chlorine, methyl, ethyl, isopropyl, trifluoromethyl, hydroxy, methoxy,ethoxy, or cyano. Most preferably, R⁸ denotes hydroxyl, or methoxy.

If R⁸ and R⁹ are bound to adjacent carbon atoms they together mayadditionally denote methylenedioxy, difluoromethylenedioxy,ethylenedioxy, C₃₋₅-alkylene, or form together with the carbon atoms towhich they are attached a benzo, pyrazino, pyrazolo, imidazo,N—(C₁₋₃-alkyl)-pyrazolo, N—(C₁₋₃-alkyl)-imidazo, triazolo, oxazolo,thiazolo, isoxazolo, or isothiazolo ring, wherein any of thefive-membered aromatics are optionally additionally monosubstituted withL and any six-membered rings are optionally mono- or disubstituted withone L and/or one substituent selected from fluorine, C₁₋₃-alkyl,trifluoromethyl, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino, hydroxyl,or C₁₋₃-alkyloxy. Preferably, R⁸ and R⁹, if bound to adjacent carbonatoms, together may additionally denote methylenedioxy,ethylene-1,2-dioxy, propylene, butylene or

together with the carbon atoms to which they are attached form a benzo,pyrazino, pyrazolo, imidazo, N—(C₁₋₁₃-alkyl)-pyrazolo,N—(C₁₋₃-alkyl)-imidazo, triazolo, oxazolo, thiazolo, isoxazolo, orisothiazolo ring, wherein any of the five-membered aromatics areoptionally additionally monosubstituted with L and any six-memberedrings are optionally mono- or disubstituted with one L and/or onesubstituent selected from fluorine, methyl, trifluoromethyl,methylamino, dimethylamino, hydroxyl, or methoxy.

More preferably, R⁸ and R⁹, if bound to adjacent carbon atoms, togethermay additionally denote methylenedioxy or ethylene-,12-dioxy or togetherwith the carbon atoms to which they are attached form a benzo, pyrazino,imidazo, N—(C₁₋₃-alkyl)-imidazo, triazolo, oxazolo, or thiazolo ring,wherein the benzo and pyrazino ring are optionally substituted with oneor two methyl groups and the imidazo, N—C₁₋₃-alkylimidazo, oxazolo, andthiazolo ring are optionally additionally substituted with L.

Most preferably, R⁸ and R⁹, if bound to adjacent carbon atoms, togethermay additionally de-note methylenedioxy or together with the carbonatoms to which they are attached form an optionally additionally withmethyl, tert-butyl, cyclopropyl, tetrahydrofuran-2-yl,1-acetyl-piperidin-4-yl, pyridin-3-yl,1,2-dihydro-1-methyl-2-oxo-pyridin-5-yl, pyridazin-4-yl, pyrazinyl, or5-methyl-pyrazin-2-yl substituted oxazolo, imidazo, or N-methyl-imidazogroup, an optionally with methyl substituted triazolo group, or anoptionally methyl or dimethyl substituted benzo or pyrazino ring.

L preferably is fluorine, C₁₋₄-alkyl, C₃₋₆-cycloalkyl, pyrrolidinyl,1-methyl-pyrrolidinyl, 1-acetyl-pyrrolidinyl, piperidinyl,1-methyl-piperidinyl, 1-acetyl-piperidinyl, tetrahydrofuranyl,tetrahydropyranyl, trifluoromethyl, cyano, amino, acetylamino,methylsulfonylamino, carboxy, C₁₋₃-alkyloxycarbonyl, aminocarbonyl,methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, hydroxy,C₁₋₃-alkyloxy, or

phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl,1,2-dihydro-2-oxo-pyridinyl, which are optionally substituted with oneor two groups independently selected from fluorine, chlorine,C₁₋₃-alkyl, difluoromethyl, trifluoromethyl, cyano, amino, acetylamino,methylsulfonylamino, carboxy, C₁₋₃-alkyloxycarbonyl, aminocarbonyl,methylaminocarbonyl, dimethylamino-carbonyl, hydroxy, methoxy,difluoromethoxy, and trifluoromethoxy.

More preferably, L is fluorine, methyl, ethyl, tert-butyl,C₃₋₆-cycloalkyl, pyrrolidinyl, 1-methyl-pyrrolidinyl,1-acetyl-pyrrolidinyl, piperidinyl, 1-methyl-piperidinyl,1-acetyl-piperidinyl, tetrahydrofuranyl, tetrahydropyranyl,trifluoromethyl, cyano, amino, acetylamino, methylsulfonylamino,carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl,methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, hydroxy,methoxy, or phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl,1,2-dihydro-2-oxo-pyridinyl, which are optionally substituted with oneor two groups independently selected from fluorine, methyltrifluoromethyl, cyano, amino, acetylamino, methylsulfonylamino,carboxy, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl,hydroxy, and methoxy.

Most preferably, L is fluorine, methyl, cyclopropyl,1-acetyl-piperidinyl, tetrahydrofuranyl, acetylamino,methylsulfonylamino, carboxy, hydroxy, methoxy, or

pyridyl, pyridazinyl, pyrazinyl, 1,2-dihydro-2-oxo-pyridinyl, which areoptionally substituted with one or two methyl groups; particularly, L ismethyl, tert-butyl, cyclopropyl, tetrahydrofuran-2-yl,1-acetyl-piperidin-4-yl, pyrid-3-yl, pyridazin-3-yl, pyrazinyl,5-methylpyrazin-2-yl, 1,2-dihydro-2-oxo-pyridin-5-yl.

R¹⁰ preferably denotes fluorine, chlorine, bromine, C₁₋₃-alkyl,difluoromethyl, trifluoromethyl, cyano, nitro, amino, acetylamino,methylsulfonylamino, carboxy, C₁₋₄-alkyloxycarbonyl, aminocarbonyl,C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl, aminosulfonyl,methylsulfanyl, methylsulfinyl, methylsulfonyl, phenyl, hydroxy,C₁₋₃-alkyloxy, difluoromethoxy, or trifluoromethoxy.

More preferably, R¹⁰ denotes fluorine, chlorine, methyl, difluoromethyl,trifluoromethyl, cyano, hydroxy, methoxy, difluoromethoxy, ortrifluoromethoxy, most preferably, R¹⁰ denotes methyl.

R¹¹ preferably denotes fluorine, C₁₋₃-alkyl, phenyl, hydroxy,C₁₋₃-alkyloxy, cyano, carboxy, C₁₋₄-alkyloxycarbonyl, aminocarbonyl,C₁₋₄-alkylamino-carbonyl, di-(C₁₋₄-alkyl)-aminocarbonyl,hydroxy-C₁₋₄-alkyl, or C₁₋₃-alkyloxy-C₁₋₄-alkyl. More preferably R¹¹denotes fluorine, C₁₋₃-alkyl, hydroxyl, or C₁₋₃-alkyloxy. Mostpreferably, R¹¹ denotes methyl, ethyl, propyl, hydroxy, or methoxy,particularly hydrogen, methyl, or methoxy.

R¹² preferably denotes fluorine, or C₁₋₃-alkyl, more preferably methylor ethyl; and

R¹³ and R¹⁴, which may be identical or different, preferably denoteC₁₋₁₃-alkyl. More preferably, R¹³ and R¹⁴ denote methyl.

Some terms used above and hereinafter to describe the compoundsaccording to the invention will now be defined more closely.

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valence isnot exceeded, and that the substitution results in a stable compound.

The term halogen denotes an atom selected from the group consisting ofF, Cl, Br and I.

The term C_(1-n)-alkyl, wherein n may have a value of 1 to 18, denotes asaturated, branched or unbranched hydrocarbon group with 1 to n C atoms.Examples of such groups include methyl, ethyl, n-propyl, iso-propyl,butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl,neo-pentyl, tert-pentyl, n-hexyl, iso-hexyl, etc.

The term C_(2-n)-alkenyl, wherein n has a value of 3 to 6, denotes abranched or unbranched hydrocarbon group with 2 to n C atoms and a C═Cdouble bond. Examples of such groups include ethenyl, 1-propenyl,2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl etc.

The term C_(2-n)-alkynyl, wherein n has a value of 3 to 6, denotes abranched or unbranched hydrocarbon group with 2 to n C atoms and a C≡Ctriple bond. Examples of such groups include ethynyl, 1-propynyl,2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,5-hexynyl etc. Unless otherwise stated alkynyl groups are connected tothe remainder of the molecule via the C atom in position 1. Thereforeterms such as 1-propynyl, 2-propynyl, 1-butynyl, etc. are equivalent tothe terms 1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl, etc. This alsoapplies analogously to C_(2-n)-alkenyl groups.

The term C_(1-n)-alkoxy denotes a C_(1-n)-alkyl-O group, whereinC_(1-n)-alkyl is as hereinbefore defined. Examples of such groupsinclude methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy,sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy,tert-pentoxy, n-hexoxy, iso-hexoxy, etc.

The term C_(1-n)-alkylcarbonyl denotes a C_(1-n)-alkyl-C(═O) group,wherein C_(1-n)-alkyl is as hereinbefore defined. Examples of suchgroups include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl,iso-propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl,sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl,iso-pentylcarbonyl, neo-pentylcarbonyl, tert-pentylcarbonyl,n-hexylcarbonyl, iso-hexylcarbonyl, etc.

The term C_(3-n)-cycloalkyl denotes a saturated mono-, bi-, tri- orspirocarbocyclic group with 3 to n C atoms. Examples of such groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, cyclododecyl, bicyclo[3.2.1.]octyl,spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl, etc.Preferably the term C₃₋₇-cycloalkyl denotes saturated monocyclic groups.

The term C_(3-n)-cycloalkenyl denotes a C_(3-n)-cycloalkyl group whichis as hereinbefore defined and additionally has at least one C═C doublebond.

The term C_(3-n)-cycloalkylcarbonyl denotes a C_(3-n)-cycloalkyl-C(═O)group wherein C_(3-n)-cycloalkyl is as hereinbefore defined.

The term tri-(C₁₋₄-alkyl)silyl comprises silyl groups which haveidentical or two or three different alkyl groups.

The term di-(C₁₋₃-alkyl)amino comprises amino groups which haveidentical or two different alkyl groups.

If groups or residues are optionally substituted, this applies to anyform of the group or residue. For instance, if an alkyl group isoptionally mono- or polyfluorinated this comprises also alkyl residueswhich are part of larger groups, e.g. alkyloxy, alkylcarbonyl,alkoxyalkyl, etc. or if a (het)aryl group is optionally mono- orpolysubstituted with a certain substituent or a set of substituents thisalso includes (het)aryl groups which are part of larger groups, e.g.(het)aryl-C_(1-n)-alkyl, (het)aryloxy, (het)aryloxy-C_(1-n)-alkyl,(het)aryl-C_(1-n)-alkyloxy, etc. Accordingly, in cases where R⁴ or R⁷have e.g. the meaning (het)aryloxy, while (het)aryl residues areoptionally mono- or polyfluorinated and (het)aryl denotes inter aliaphenyl, the meanings mono-, di-, tri-, tetra-, and pentafluoro-phenoxyare also comprised. The same applies to groups or residues in which aCH₂ group may be replaced by O, S, NR, CO, or SO₂. For instance, aresidue having inter alia the meaning hydroxy-C₁₋₃-alkyl, in which a CH₂group may be replaced by CO, this comprises carboxy, carboxymethyl,hydroxymethylcarbonyl, carboxyethyl, hydroxymethylcarbonylmethyl, andhydroxyethyl-carbonyl.

The compounds according to the invention may be obtained using methodsof synthesis known in principle. Preferably the compounds are obtainedby the following methods according to the invention which are describedin more detail hereinafter.

A general strategy to access compounds of the invention is delineated inScheme 1; R², R³, X, m, n, and o have the meanings as definedhereinbefore and hereinafter. The key reaction to assemble the bicyclicframework is an intramolecular merger of an amino functionality with acarboxy group that results in the formation of an amide linkage. Thefusion of the carboxylic acid function and the amino group may becarried out with or without an additive at elevated temperatures,preferably between 20 and 200° C. Additives that remove the waterforming during the reaction, such as molecular sieves or orthoesters, orother additives such as bases, e.g. hexamethyldisilazides, or boronicacids may facilitate the reaction. Though, more preferably the reactionis done with a more reactive entity of the carboxy function such as anacyl halide, ester, thioester, anhydride, mixed anhydride, or ketenewhich may be generated in a separate preceding reaction step or in situ.Preferred acyl halides are acyl chloride and acyl fluoride. Preferredesters and thioesters are derived from e.g. methanol/methylthiol,ethanol/ethylthiol, 2,2,2-trifluoroethanol, phenol/thiophenol,substituted phenol/thiophenol such as 4-nitrophenol orpentafluorophenol, hydroxy heteroaryl such as hydroxybenzotriazol,hydroxypyridotriazol, or hydroxytriazines, or N-hydroxysuccinimid.Preferred mixed anhydrides are derived from alkylcarboxylic acids, e.g.pivalic acid, carbonates, e.g. methyl and ethyl carbonate, carbamates,e.g. N,N-dimethyl carbamate, phosphoric acids, e.g. dimethyl-phosphoricacid or (Me₂N)₂P(O)OH, or ureas, e.g. dicyclohexylurea, dimethylurea, ortetramethylurea. Additionally, N acylated derivatives derived fromazaheteroaromatics such as imidazole, triazole, tetrazole, or pyridinesuch as e.g. 4-dimethylaminopyridine may be used as well. Some of themore popular reagents used for the activation of the carboxylic acidfunction are N,N′-carbonyldiimidazol, dicyclohexylcarbodiimide,(benzotriazol-1-yloxy)-dipiperidinocarbenium hexafluorophospate ortetrafluoroborate, (benzotriazol-1-yloxy)dipyrrolidinocarbeniumhexafluorophospate or tetrafluoroborate,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide, POCl₃, SOCl₂,(COCl)₂, COCl₂, arylboronic acid, TiCl₄, (MeO)₂POCl, cyanuric chloride,1-hydroxybenzotriazol, 1-hydroxy-7-azabenzotriazol,benzol-triazol-1-yloxytris(dimethylamino)phosphonium hexafluorophospateor tetrafluoroborate, benzoltriazol-1-yloxytripyrrolidinophosphoniumhexafluorophospate or tetrafluoroborate,(7-aza-benzoltriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate or tetrafluoroborate,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphateor tetra-fluoroborate,O-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate or tetrafluoroborate. This compilation of reagentsrepresents only a few possibilities to activate an carboxylic acidfunction. A host of additional reagents is known and may be used here aswell. The reactive carboxylic acid derivatives may also serve asintermediates for other acylating reagents also sufficiently reactivefor this transformation. The activation step and the ensuing amideforming step are often best carried out in the presence of additionaladditives such as bases, e.g. ethyldiisopropylamine, triethylamine,alkali metal carbonate, pyridine, 4-dimethylaminopyridine, imidazole,dimethylaluminum amides, lithium amides, alkali metal cyanide, or alkalimetal hexamethyldisilazide. The reactions are preferably con-ducted inorganic solvents but may also be carried out in aqueous solvents. Amongthe organic solvents ordinarily used are dimethylformamide,dimethylacetamide, N-methyl-pyrrolidinone, dimethylsulfoxide,tetrahydrofuran, hexane, ether, dioxane, dimethoxyethane,dichloromethane, dichloroethane, toluene, benzene, ethyl acetate,quinoline, pyridine, or mixtures thereof. The reactions may be carriedout at −80° C. to 220° C., preferably between −10° C. and 120° C.Subsequently, the lactam group is reduced to give the secondary amine.This transformation is a well established reaction that may be carriedout, for example, using LiAlH₄, hydrogen in the presence of a catalyst,NaBH₄ in the presence of e.g. iodine, LiBH₄, borane, sodium in propanol,Cl₃SiH, silanes, e.g. Et₃SiH, in the presence of a transition metal suchas rhenium, 9-BBN, LiBH₃NMe₂, or Et₃SiH combined with LiEt₃BH. Solventssuch as e.g. tetrahydrofuran, ether, dimethoxyethane, dioxane, hexane,benzene, toluene, dichloro-methane, alcohols, water, or mixtures thereofmay be employed at −78° C. to 200° C., preferably between −10° C. and120° C.; though, in combination with some reducing reagents only a fewof these solvents are usable. This strategy is well suited for thesynthesis of the scaffolds I.1 to I.10.

Another common synthetic route to acquire the compounds of the inventionis summarized in Scheme 2; R², R³, X, m, n, and o have the meanings asdefined hereinbefore and herein-after. The bicyclic framework is formedvia an intramolecular reductive amination reaction of a primary aminewith a ketone functionality. Reductive aminations have large precedencein organic chemistry and may be carried out e.g. using hydrogen in thepresence of a transition metal catalyst such as one derived from Ni, Rh,Pd, or Pt, borohydride reagents, e.g. sodium borohydride, sodiumcyanoborohydride, or sodium triacetoxyborohydide, zinc in combinationwith hydrochloric acid, PhSiH₃ with Bu₂SnCl₂, B₁₀H₁₄, or formic acid orsalts thereof. Some of these reagents are preferably used in combinationwith an additive such as acid, e.g. acetic acid or mineral acid. Thereactions are preferably conducted in organic solvents or aqueousmixtures, e.g. dimethylformamide, dimethylacetamide,N-methylpyrrolidinone, dimethylsulfoxide, tetrahydrofuran, hexane,ether, dioxane, dimethoxyethane, dichloromethane, dichloro-ethane,toluene, benzene, alcohols, water, or mixtures thereof. The reactionsmay be carried out at −80° C. to 200° C., preferably between −10° C. and100° C.

The strategy shown in Scheme 3, wherein R², R³, X, m, n, and o have themeanings as defined hereinbefore and hereinafter, is another validapproach based on the reductive amination reaction already delineated inScheme 2. Reaction conditions described there may analogously beemployed here.

Scheme 4, wherein R², R³, X, m, n, and o have the meanings as definedhereinbefore and hereinafter, shows another approach to assemble thebicyclic framework. This approach is an intramolecular alkylation of thenitrogen group with an appropriate electrophile of the side-chain. Thenitrogen group may be an amino group, i.e. R^(a) denotes e.g. hydrogen,methyl, allyl, benzyl, or dimethoxybenzyl, or an amide group, i.e. R^(a)denotes e.g. methoxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl,tertbutoxycarbonyl, trifluormethylcarbonyl, acetyl,2,2,2-trichloroethoxycarbonyl, tolylsulfonyl, phenylsulfonyl,methoxyphenylsulfonyl, nitrophenyl-sulfonyl,2,2,2-trichloroethylsulfonyl, or 2-trimethylsilylethylsulfonyl. Thenitrogen function is reacted with an electrophilic C_(sp3)-center in theside-chain, i.e. LG in Scheme 4 denotes e.g. chlorine, bromine, iodine,mesyloxy, tosyloxy, or trifluoromethylsulfonyloxy, in the presence of abase such as e.g. triethylamine, ethyldiisopropylamine,diazabicycloundecene, alkali metal carbonate, alkali metal tertbutoxide,alkali metal diisopropylamide, butyllithium, or sodium hydride. Thestronger bases among them are preferably used in combination with theamides in e.g. N-methylpyrrolidinone, dimethylsulfoxide,tetrahydrofuran, hexane, ether, dioxane, dimethoxyethane, toluene,benzene, tertbutanol, isopropanol, or mixtures thereof at temperaturesbetween −70 and 100° C., preferably between −30 and 60° C. The milderbases listed are preferably used in combination with the amines indichloromethane, dimethylformamide, N-methylpyrrolidinone,dimethylsulfoxide, tetrahydrofuran, hexane, ether, dioxane,dimethoxyethane, toluene, benzene, methanol, ethanol, tertbutanol,isopropanol, water, or mixtures thereof at temperatures between 0 and140° C., preferably between 20 and 120° C. For the amides the conditionsoriginally reported by Mitsunobu may be used as well. Accordingly, theside-chain leaving group LG is generated in situ from the hydroxy group(LG=OH) using a phosphine, e.g. triphenylphosphine or tributylphosphine,in combination with an azodicarboxylate, e.g. diethyl azodicarboxylate,diisopropyl azodicarboxylate, or azodicarboxylic dipiperidide. Suitedsolvents may be selected from among dimethylformamide,N-methylpyrrolidinone, dichloromethane, tetrahydrofuran, hexane, ether,dioxane, dimethoxyethane, toluene, benzene, and mixtures thereof. Thereaction is preferably conducted at temperatures between 0 and 100° C.The opposite way around, i.e. LG denotes NHR^(a) and NHR^(a) denotes LG,may be applicable as well. Reaction conditions are equivalent to theoriginal way around.

A further generally applicable approach is based on an electrophilicaromatic substitution reaction (Scheme 5); R², R³, m, n, and o have themeanings as defined hereinbefore and hereinafter. Thereby the aromaticpart of the molecule reacts with an activated carbon atom of theazacycle to form the bicyclic framework. The reactive intermediate bearsa (partially) positively charged carbon atom in the azacycle that may begenerated by the addition of an acid to an olefinic bond or by theactivation of an appropriately positioned leaving group. A huge numberof Bronstedt and Lewis acids have been described for this classicalreaction that may also be used here. The following enumeration issupposed to give a few more widely used of them: hydrobromic acid,hydroiodic acid, hydrochloric acid, sulfuric acid, phosphoric acid,P₄O₁₀, trifluoroacetic acid, methanesulfonic acid, toluenesulfonic acid,trifluormethanesulfonic acid, Sc(OTf)₃, SnCl₄, FeCl₃, AlBr₃, AlCl₃,SbCl₅, BCl₃, BF₃, ZnCl₂, montmorillonites, POCl₃, and PCl₅. Depending onthe inclination of the leaving group to be substituted and theelectronic nature of the aromatic a more or less powerful acid catalysthas to be used. Besides the acid catalysts mentioned silver salts, e.g.AgOTf, may be useful in the reactions using halides as leaving group.Preferred solvents are hydrocarbons such as hexane or cyclohexane,chlorinated hydrocarbons such as dichloromethane or dichloro-ethane,perfluorinated hydrocarbons, nitrobenzene, chlorinated benzenes,heteroaromatics such as quinoline, dimethoxyethane, dioxane, ether,ionic liquids, or mixtures thereof. The reactions may be carried outbetween −10° C. and 220° C., preferably between 20° C. and 180° C. Thereactions may also be conducted under microwave irradiation.

This synthetic strategy is particularly suited for the scaffolds I.1 andI.3 to I.10 bearing an electron rich aromatic.

The bicyclic scaffold may also be accessed via the route delineated inScheme 6; m has the meaning as defined hereinbefore and hereinafter andPG and PG′ are protective groups such as e.g. trialkylsilyl for PG andbenzyl or methyl for PG′. The cyclization is realized by the addition ofa radical intermediate, generated from the trichloromethyl group and achlorine abstracting reagent, onto the double bond. Suited chlorineabstracting reagents are Bu₃Sn. and (Me₃Si)₃Si. that are formed in situby a radical initiator, such as azobisisobutyronitrile ordibenzoylperoxide, from Bu₃SnH and (Me₃Si)₃SiH, respectively. Thereaction is preferably conducted in benzene, toluene, cyclohexane, orhexanes at elevated temperature. This approach is reported inter alia inTetrahedron: Asymmetry 1999, 10, 2399-2410. Elaboration of the bicyclicscaffold to the desired compounds may be accomplished after reduction ofthe amide functionality to the amine and removal of the protecting groupat the right-hand end of the molecule and transformation of the CH₂C═Osubstructure in the left-hand part of the molecule to one of thearomatics described hereinbefore. These transformations are describedhereinbefore and hereinafter and are known for similar compounds fromthe organic chemistry literature (see e.g. Thomas L. Gilchrist,Heterocyclenchemie, VCH, Weinheim, 1995).

Besides the strategies presented a host of additional approaches toconstruct the bicyclic systems of the present invention can be envisagedand are also reported in the literature (see e.g. J. Med. Chem. 1970,13, 630-634; Chem. Rev. 1977, 77, 1-36; J. Med. Chem. 1979, 22, 537-553;J. Org. Chem. 1984, 49, 4033-4044; J. Med. Chem. 1996, 39, 1956-1966;Heterocycles 1996, 43, 15-22; J. Med. Chem. 2002, 45, 3755-3764; J. Org.Chem. 2006, 71, 2046-2055; and references quoted therein). Therefore,the preceding strategies are in no way meant to restrict the possiblesynthetic pathways to access the compounds of the invention but are onlysupposed to show a few routes by way of example.

The synthetic routes presented may rely on the use of protecting groups.Suitable protecting groups for the respective functionalities and theirremoval have been described hereinbefore and may analogously be employed(see also: Protecting Groups, Philip J. Kocienski, 3^(rd) edition, GeorgThieme Verlag, Stuttgart, 2004 and references quoted therein).

The compounds according to the invention are advantageously alsoobtainable using the methods described in the examples that follow,which may also be combined for this purpose with methods known to theskilled man from the literature.

As already mentioned, the compounds of general formula I according tothe invention and the physiologically acceptable salts thereof havevaluable pharmacological properties, particularly an inhibitory effecton the enzyme 11β-hydroxysteroid dehydrogenase (HSD) 1.

The biological properties of the new compounds may be investigated asfollows:

In vitro inhibition of 11β-HSD1 by test compounds was determined withHTRF (Homogeneous Time-Resolved Fluorescence) technology (cisbiointernational, France) detecting cortisol generated from cortisterone byhuman liver microsomes. Briefly, compounds were incubated for 1 hour at37° C. in Tris buffer (20 mM tris, 5 mM EDTA, pH 6.0) containing NADPH(200 μM) and cortisone (80 nM). Cortisol generated in the reaction isthen detected with a competitive immunoassay, involving two HTRFconjugates: cortisol linked to XL665 and anti-cortisol antibody labeledwith Europium cryptate. The incubation period for detection reaction wastypically 2 hours. The amount of cortisol is determined by reading thetime-resolved fluorescence of the wells (Ex 320/75 nm; Em 615/8.5 nm and665/7.5 nm). The ratio of the two emission signals is then calculated(Em665*10000/Em615). Each assay contained incubations with vehiclecontrols instead of compound as controls for non-inhibited cortisolgene-ration (100% CTL; ‘high values’) and incubations with carbenoxoloneas controls for fully inhibited enzyme and cortisol background (0% CTL;‘low values’). Each assay also contained a calibration curve withcortisol to transform the fluorescent data into cortisol concentrations.Percent inhibition of each compound was determined relative to thecarbenoxolone signal and IC₅₀ curves were generated.

The compounds of general formula I according to the invention may forexample have IC₅₀ values below 10000 nM, particularly below 1000 nM,most preferably below 100 nM. In the Table 2 compounds of the invention(specified in Table 3) and their inhibitory activity determined asdescribed above are compiled.

TABLE 2 11β- HSD Ex. 11β-HSD Ex. 11β-HSD Ex. 11β-HSD Ex. IC₅₀ No. IC₅₀(nM) No. IC₅₀ (nM) No. IC₅₀ (nM) No. (nM) 1 285 80 40 168 561 249 265 2741 81 463 169 950 250 53 3 85 82 56 170 626 251 66 4 56 84 139 171 1651252 61 5 3099 85 89 172 1724 253 78 6 1058 86 2399 173 1694 254 742 7262 87 622 174 406 255 742 8 3356 88 171 175 344 256 222 9 1979 89 62176 603 257 209 10 1775 90 468 177 8906 258 33 11 530 91 711 178 159 259115 12 792 92 1106 179 199 260 181 13 1609 93 2058 180 1318 261 47 14734 94 6723 181 147 262 73 15 354 95 3842 183 155 263 71 16 360 96 95184 1147 264 78 17 1378 97 1134 185 5375 265 22 18 3685 98 125 187 1957266 42 19 658 99 285 188 2916 267 66 20 254 100 564 189 2273 268 931 21669 102 1459 190 1651 269 63 22 5042 103 86 191 571 270 99 24 134 1041388 192 434 271 50 25 686 105 1332 193 360 272 44 26 2889 106 2961 194642 273 35 27 629 107 2546 195 2479 274 51 28 3684 108 140 196 781 27525 29 1727 109 1457 197 3830 276 34 30 1398 111 1604 198 435 277 34 3188 112 1234 199 137 278 438 32 915 113 3633 200 117 279 52 33 3493 1151587 201 53 280 1264 34 3883 116 3854 202 66 281 918 35 672 117 1423 203125 282 409 36 3665 118 72 204 27 283 55 37 998 119 1548 205 38 284 66638 1444 120 3843 206 47 285 150 39 1590 121 4122 207 224 286 47 40 542122 818 208 238 287 61 41 589 123 297 209 40 288 901 42 4527 124 658 21068 289 121 43 1757 125 989 211 31 290 72 44 200 126 1270 212 1945 291183 45 384 127 1466 213 2972 292 502 46 97 128 1291 214 5711 293 27 48364 129 5848 215 1730 294 146 49 168 130 1608 216 1715 295 35 50 3002131 361 217 410 296 32 51 629 132 958 218 2708 297 895 52 101 133 941219 160 298 99 53 321 134 1228 220 549 299 352 54 529 135 3520 221 2433300 115 55 746 137 3621 222 124 301 32 56 725 138 2805 223 106 302 35 57137 139 92 224 21 303 717 58 62 140 48 225 98 304 251 59 36 141 59 2261410 305 153 60 228 142 689 227 25 306 978 61 798 143 123 228 236 307979 62 109 144 2561 229 68 308 210 63 216 145 108 231 146 309 184 64 753146 384 232 132 310 214 65 29 147 1013 233 144 311 424 66 822 148 556234 3119 312 103 67 32 149 374 235 95 313 61 68 372 150 438 236 189 314162 69 105 151 426 237 916 315 61 70 362 152 4668 238 24 316 32 71 47154 1657 239 24 317 217 72 148 155 354 240 51 318 31 73 88 156 340 241204 319 446 74 69 157 335 242 547 320 165 75 395 160 2175 243 113 3211167 76 166 161 1750 245 257 323 620 77 144 162 1091 246 637 324 121 7867 163 249 247 190 325 771 79 1367 167 291 248 1514 330 44 331 439 33264 333 84 334 104 335 115 336 198 337 52 338 63 339 1272 340 67 341 601342 373 343 1524 344 35In view of their ability to inhibit enzyme 11β-hydroxysteroiddehydrogenase (HSD) 1, the compounds of general formula I according tothe invention and the corresponding pharmaceutically acceptable saltsthereof are theoretically suitable for the treatment and/or preventativetreatment of all those conditions or diseases which may be affected bythe inhibition of the 11β-hydroxysteroid dehydrogenase (HSD) 1 activity.Therefore, compounds according to the invention are particularlysuitable for the prevention or treatment of diseases, particularlymetabolic disorders, or conditions such as type 1 and type 2 diabetesmellitus, complications of diabetes (such as e.g. retinopathy,nephropathy or neuropathies, diabetic foot, ulcers, macroangiopathies,slow or poor wound healing), metabolic acidosis or ketosis, reactivehypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulinresistance, metabolic syndrome, dyslipidaemias of different origins,atherosclerosis and related diseases, obesity, high blood pressure,chronic heart failure, edema and hyperuricaemia. These substances arealso suitable for preventing beta-cell degeneration such as e.g.apoptosis or necrosis of pancreatic beta cells. The substances are alsosuitable for improving or restoring the functionality of pancreaticcells, and also of increasing the number and size of pancreatic betacells. The compounds according to the invention may also be used asdiuretics or antihypertensives and are suitable for the prevention andtreatment of acute renal failure.

Additionally, inhibition of 11β-hydroxysteroid dehydrogenase (HSD) 1 hasbeen shown to lower intraocular pressure in subjects with ocularhypertension, therefore the compounds could be used to treat glaucoma.

In view of the role of 11β-hydroxysteroid dehydrogenase (HSD) 1 inmodulating cortisol levels for interaction with the glucocorticoidreceptor, and the known role of excess gluco-corticoids in bone loss,the compounds may have beneficial effects against osteoporosis.

Stress and/or glucocorticoids have been shown to influence cognitivefunction, and excess cortisol has been associated with brain neuronalloss or dysfunction. Treatment with an 11β-hydroxysteroid dehydrogenase(HSD) 1 inhibitor may result in amelioration or prevention of cognitiveimpairment. Such compounds may also be useful in treating anxiety ordepression.

The dynamic interaction between the immune system and the HPA(hypothalamopituitary-adrenal) axis is known, and glucocorticoids helpbalance between cell-mediated responses and humoral responses. Theimmune reaction is typically biased towards a humoral response incertain disease states, such as tuberculosis, leprosy, and psoriasis.More appropriate would be a cell-based response. An 11β-hydroxysteroiddehydrogenase (HSD) 1 inhibitor would bolster a temporal immune responsein association with immunization to ensure that a cell based responsewould be obtained, and as such could be useful in immunomodulation.

In particular, the compounds according to the invention, including thephysiologically acceptable salts thereof, are suitable for theprevention or treatment of diabetes, particularly type 1 and type 2diabetes mellitus, and/or diabetic complications.

The dosage required to achieve the corresponding activity for treatmentor prevention usually depends on the compound which is to beadministered, the patient, the nature and gravity of the illness orcondition and the method and frequency of administration and is for thepatient's doctor to decide. Expediently, the dosage may be from 1 to 100mg, preferably 1 to 30 mg, by intravenous route, and 1 to 1000 mg,preferably 1 to 100 mg, by oral route, in each case administered 1 to 4times a day. For this purpose, the compounds of formula I preparedaccording to the invention may be formulated, optionally together withother active substances, together with one or more inert conventionalcarriers and/or diluents, e.g. with corn starch, lactose, glucose,microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone,citric acid, tartaric acid, water, water/ethanol, water/glycerol,water/sorbitol, water/polyethylene glycol, propylene glycol,cetylstearyl alcohol, carboxymethylcellulose or fatty substances such ashard fat or suitable mixtures thereof, to produce conventional galenicpreparations such as plain or coated tablets, capsules, powders,suspensions or suppositories.

The compounds according to the invention may also be used in conjunctionwith other active substances, particularly for the treatment and/orprevention of the diseases and conditions mentioned above. Other activesubstances which are suitable for such combinations include for examplethose which potentiate the therapeutic effect of an 11β-hydroxysteroiddehydrogenase (HSD) 1 inhibitor according to the invention with respectto one of the indications mentioned and/or which allow the dosage of an11β-hydroxysteroid dehydrogenase (HSD) 1 inhibitor according to theinvention to be reduced. Therapeutic agents which are suitable for sucha combination include, for example, antidiabetic agents such asmetformin, sulfonylureas (e.g. glibenclamide, tolbutamide, glimepiride),nateglinide, repaglinide, thiazolidinediones (e.g. rosiglitazone,pioglitazone), SGLT 2 inhibitors (e.g. dapagliflozin, sergliflozin),PPAR-gamma-agonists (e.g. GI 262570) and antagonists, PPAR-gamma/alphamodulators (e.g. KRP 297), alpha-glucosidase inhibitors (e.g. acarbose,voglibose), DPPIV inhibitors (e.g. Sitagliptin, Vildagliptin,Saxagliptin, Alogliptin, BI 1356), alpha2-antagonists, insulin andinsulin analogues, GLP-1 and GLP-1 analogues (e.g. exendin-4) or amylin.The list also includes inhibitors of protein tyrosinephosphatase 1,substances that affect deregulated glucose production in the liver, suchas e.g. inhibitors of glucose-6-phosphatase, orfructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon receptorantagonists and inhibitors of phosphoenol pyruvate carboxykinase,glycogen synthase kinase or pyruvate dehydrokinase and glucokinaseactivators, lipid lowering agents such as for example HMG-CoA-reductaseinhibitors (e.g. simvastatin, atorvastatin), fibrates (e.g. bezafibrate,fenofibrate), nicotinic acid and the derivatives thereof, PPAR-alphaagonists, PPAR-delta agonists, ACAT inhibitors (e.g. avasimibe) orcholesterol absorption inhibitors such as, for example, ezetimibe, bileacid-binding substances such as, for example, cholestyramine, inhibitorsof ileac bile acid transport, HDL-raising compounds such as CETPinhibitors or ABC1 regulators or active substances for treating obesity,such as sibutramine or tetrahydrolipostatin, SDRIs, axokine, leptin,leptin mimetics, antagonists of the cannabinoid1 receptor, MCH-1receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists orβ3-agonists such as SB-418790 or AD-9677 and agonists of the 5HT2creceptor.

Moreover, combinations with drugs for influencing high blood pressure,chronic heart failure or atherosclerosis such as e.g. A-II antagonistsor ACE inhibitors, ECE inhibitors, diuretics, β-blockers,Ca-antagonists, centrally acting antihypertensives, antagonists of thealpha-2-adrenergic receptor, inhibitors of neutral endopeptidase,thrombocyte aggregation inhibitors and others or combinations thereofare suitable. Examples of angiotensin II receptor antagonists arecandesartan cilexetil, potassium losartan, eprosartan mesylate,valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312,olmesartan, medoxomil, tasosartan, KT-3-671, GA-0113, RU-64276,EMD-90423, BR-9701, etc. Angiotensin II receptor antagonists arepreferably used for the treatment or prevention of high blood pressureand complications of diabetes, often combined with a diuretic such ashydrochlorothiazide.

A combination with uric acid synthesis inhibitors or uricosurics issuitable for the treatment or prevention of gout.

A combination with GABA-receptor antagonists, Na-channel blockers,topiramat, protein-kinase C inhibitors, advanced glycation end productinhibitors or aldose reductase inhibitors may be used for the treatmentor prevention of complications of diabetes.

The dosage for the combination partners mentioned above is usefully ⅕ ofthe lowest dose normally recommended up to 1/1 of the normallyrecommended dose.

Therefore, in another aspect, this invention relates to the use of acompound according to the invention or a physiologically acceptable saltof such a compound combined with at least one of the active substancesdescribed above as a combination partner, for preparing a pharmaceuticalcomposition which is suitable for the treatment or prevention ofdiseases or conditions which can be affected by inhibiting the enzyme11β-hydroxysteroid dehydrogenase (HSD) 1. These are preferably metabolicdiseases, particularly one of the diseases or conditions listed above,most particularly diabetes or diabetic complications.

The use of the compound according to the invention, or a physiologicallyacceptable salt thereof, in combination with another active substancemay take place simultaneously or at staggered times, but particularlywithin a short space of time. If they are administered simultaneously,the two active substances are given to the patient together; while ifthey are used at staggered times the two active substances are given tothe patient within a period of less than or equal to 12 hours, butparticularly less than or equal to 6 hours.

Consequently, in another aspect, this invention relates to apharmaceutical composition which comprises a compound according to theinvention or a physiologically acceptable salt of such a compound and atleast one of the active substances described above as combinationpartners, optionally together with one or more inert carriers and/ordiluents.

Thus, for example, a pharmaceutical composition according to theinvention comprises a combination of a compound of formula I accordingto the invention or a physiologically acceptable salt of such a compoundand at least one angiotensin II receptor antagonist optionally togetherwith one or more inert carriers and/or diluents.

The compound according to the invention, or a physiologically acceptablesalt thereof, and the additional active substance to be combinedtherewith may both be present together in one formulation, for example atablet or capsule, or separately in two identical or differentformulations, for example as a so-called kit-of-parts.

The Examples that follow are intended to illustrate the presentinvention without restricting it:

Preparation of the Starting Compounds Example I

4-Methyl-2-phenylethynyl-pyridine

Phenylacetylene (15.4 mL) is added to a mixture of2-bromo-4-methyl-pyridine (20.0 g), CuI (2.2 g), and Pd(PPh₃)₂Cl₂ (4.1g) in triethylamine (600 mL) kept under argon atmosphere. The mixture isstirred at ambient temperature overnight. Then, water is added and theresulting mixture is extracted with diethylether. The combined organicextracts are washed with brine and dried (MgSO₄). The solvent is removedunder reduced pressure and the residue is purified by chromatography onsilica gel (cyclohexane/ethyl acetate 9:1->4:1) to give the product asan oil.

Yield: 18.6 g (83% of theory)

Mass spectrum (ESI⁺): m/z=194 [M+H]⁺

Example II

4-Methyl-2-phenethyl-pyridine

A mixture of 4-methyl-2-phenylethynyl-pyridine (18.2 g) and 10%palladium on carbon (2.0 g) in methanol (300 mL) is stirred underhydrogen atmosphere (50 psi) at ambient temperature until the triplebond is completely reduced (20 h). The mixture is filtered and thesolvent is removed under reduced pressure.

Yield: 17.6 g (95% of theory)

Mass spectrum (ESI⁺): m/z=198 [M+H]⁺

Example III

1,4-Dimethyl-2-phenethyl-pyridinium iodide

Iodomethane (8.3 mL) is added to a solution of4-methyl-2-phenethyl-pyridine (17.5 g) in acetonitrile (70 mL). Theresulting solution is stirred at room temperature overnight beforeanother portion of iodomethane (2.8 mL) is added and the solution isfurther stirred at ca. 35° C. for another 14 h. After cooling to roomtemperature, the precipitate is separated by filtration, washed withacetonitrile, and dried at 50° C.

Yield: 20.9 g (69% of theory)

Mass spectrum (ESI⁺): m/z=212 [1,4-dimethyl-2-phenethyl-pyridinium]⁺

Example IV

1,4-Dimethyl-6-phenethyl-1,2,3,6-tetrahydro-pyridine and1,4-dimethyl-2-phenethyl-1,2,3,6-tetrahydro-pyridine

Sodium borohydride (2.9 g) is added in one portion to a mixture of1,4-dimethyl-2-phenethyl-pyridinium iodide (20.9 g) and sodium hydroxide(23.9 g) in water (60 mL) and methanol (75 mL). The mixture is stirredat 60° C. for 1 h and then cooled to room temperature. The reactionmixture is extracted with diethylether and the organic extracts aredried (MgSO₄). After removing the solvent, the residue is purified bychromatography on silica gel (dichloromethane/methanol 30:1->9:1) togive a mixture of the two title products (ca. 3:1).

Yield: 16.4 g (61% of theory)

Mass spectrum (ESI⁺): m/z=216 [M+H]⁺

Example V

1,11-Dimethyl-11-aza-tricyclo[8.3.1.0*2,7*]tetradeca-2,4,6-triene

A mixture of 1,4-dimethyl-6-phenethyl-1,2,3,6-tetrahydro-pyridine and1,4-dimethyl-2-phenethyl-1,2,3,6-tetrahydro-pyridine (ca. 3:1, 1.0 g)dissolved in polyphosphoric acid (5 mL) is stirred at 150° C. for 2 d.After cooling to ca. 80° C., water (30 mL) is added and the mixture isstirred vigorously for another 5 min. Then, the mixture is cooled in anice bath, more water is added, and the mixture is basified using 40%NaOH in water. The resulting mixture is extracted with ethyl acetate,the combined organic extracts are washed with brine and dried (MgSO₄).The solvent is removed under reduced pressure to yield the titleproduct.

Yield: 0.76 g (76% of theory)

Mass spectrum (ESI⁺): m/z=216 [M+H]⁺

The following compound is obtained analogously to Example V:

(1) 1-Methyl-10-aza-tricyclo[7.2.1.0*2,7*]dodeca-2,4,6-triene

Mass spectrum (ESI⁺): m/z=174 [M+H]⁺

2-Benzyl-4-methyl-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl esteris used as the starting material.

Example VI

1-Methyl-11-aza-tricyclo[8.3.1.0*2,7*]tetradeca-2,4,6-triene

1-Chloroethyl chloroformate (3.8 mL) is added dropwise to a mixture of1,11-dimethyl-11-aza-tricyclo[8.3.1.0*2,7*]tetradeca-2,4,6-triene (0.75g) and NaHCO₃ (2.9 g) in 1,2-dichloroethane (3.5 mL) chilled in an icebath. The reaction mixture is warmed to room temperature in the coolingbath and stirred overnight. Then, dichloromethane (20 mL) is added andthe precipitate is removed by filtration. The filtrate is concentratedunder reduced pressure and the residue is dissolved in methanol (20 mL).The resulting solution is stirred at reflux temperature for 2 h. Thesolution is concentrated and the residue is purified by HPLC on reversedphase (water/MeCN/NH₃) to give the title compound.

Yield: 0.11 g (16% of theory)

The following compounds are obtained analogously to Example VI:

(1) 11,11-Dimethyl-2,3,4,5-tetrahydro-1H-2,6-methano-benzo[d]azocin-6-ol

The starting material,3,11,11-trimethyl-2,3,4,5-tetrahydro-1H-2,6-methano-benzo[d]azocin-6-ol,is obtained in analogy to EP 28717 (1981) from2-benzyl-1,3,3-trimethyl-piperidinone.

(2)8-Hydroxy-2,3,4,5-tetrahydro-1H-2,6-methano-benzo[d]azocine-6-carboxylicacid methyl ester

The starting material,8-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-2,6-methano-benzo[d]azocine-6-carboxylicacid methyl ester, may be obtained in analogy to J. Med. Chem. 1962, 5,357-361 and U.S. Pat. No. 3,687,957 (1972) from8-methoxy-3-methyl-1-oxo-2,3,4,5-tetrahydro-1H-2,6-methano-benzo[d]azocine-6-carbonitrile.The methoxy group on the aromatic ring may be cleaved by using borontribromide in dichloromethane or hydrobromic acid in acetic acid (seee.g. J. Med. Chem. 1992, 35, 4135-4142; J. Med. Chem. 2004, 47,165-174).

The starting material may also be obtained by reacting compound ExampleXXII(1) with boron tribromide according to Procedure J.

(3)11,11-Dimethyl-6-phenyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-ol

The starting material,3,11,11-trimethyl-6-phenyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-ol,may be obtained as described in DE 2027077 (1970).

(4) 6-Propyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-ol

The starting material,3-methyl-6-propyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-01,may be obtained as described in J. Med. Chem. 1963, 6, 322-5.

(5) 6-Methyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-ol

The starting material,3,6-Dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-ol, maybe obtained as described in J. Org. Chem. 1960, 25, 1386-8.

Example VII

(6-Methoxy-3-oxo-indan-1-yl)-acetic acid methyl ester

Concentrated sulfuric acid (3.0 mL) is added to5-methoxy-1-indanone-3-acetic acid (13.0 g) dissolved in methanol (100mL). The solution is stirred at reflux temperature for 4 h and thencooled to room temperature. About two third of the methanol is removedunder reduced pressure and water (100 mL) and ethyl acetate (200 mL) areadded to the remainder. The organic phase is separated and washed withwater, 1 M NaOH solution, and brine. The organic phase is dried (MgSO₄)and the solvent is evaporated to give the product as a yellow oil.

Yield: 13.2 g (95% of theory)

Mass spectrum (ESI⁺): m/z=235 [M+H]⁺

Example VIII

(3-Hydroxyimino-6-methoxy-indan-1-yl)-acetic acid methyl ester

(6-Methoxy-3-oxo-indan-1-yl)-acetic acid methyl ester (12.0 g),hydroxylamine hydrochloride (4.6 g), and sodium acetate (5.5 g)dissolved in water (40 mL) and methanol (50 mL) are stirred at refluxtemperature for 3 h. After cooling to room temperature, water (100 mL)is added and the solution is extracted with ethyl acetate. The combinedorganic extracts are washed with water and brine and dried (MgSO₄). Thesolvent is evaporated to give the product as a brown oil.

Yield: 12.5 g (98% of theory)

Mass spectrum (ESI⁺): m/z=250 [M+H]⁺

Example IX

5-Methoxy-3-methoxycarbonylmethyl-indan-1-yl-ammonium chloride

A mixture of 10% palladium on carbon (3.0 g),(3-hydroxyimino-6-methoxy-indan-1-yl)-acetic acid methyl ester (12.5 g),and concentrated hydrochloric acid (4.7 mL) in methanol (150 mL) isstirred under hydrogen atmosphere at room temperature overnight. Themixture is filtered and the filtrate is concentrated under reducedpressure. The residue is azeotropically dried using toluene and washedwith diisopropylether to give the product as a white solid after dryingat 50° C.

Yield: 13.0 g (100% of theory)

Mass spectrum (ESI⁺): m/z=236 [M+H](of amine)

Example X

3-Carboxymethyl-5-methoxy-indan-1-yl-ammonium chloride

5-Methoxy-3-methoxycarbonylmethyl-indan-1-yl-ammonium chloride (12.5 g)dissolved in 2 M hydrochloric acid (120 mL) is stirred at refluxtemperature for 3 h. Then, the solvent is removed and the residue isazeotropically dried using toluene and further purified by washing withdiisopropylether. The product is dried at 50° C.

Yield: 11.8 g (100% of theory)

Mass spectrum (ESI⁺): m/z=220 [M+H]⁺ (of amine)

Example XI

4-Methoxy-9-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-10-one

3-Carboxymethyl-5-methoxy-indan-1-yl-ammonium chloride (13.2 g) and1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide methyl-p-toluenesulfonate(21.7 g) dissolved in pyridine (500 mL) is stirred at room temperaturefor 7 d. Then, the pyridine is removed under reduced pressure and theresidue is taken up in water (200 mL) and dichloromethane (200 mL). Theorganic phase is separated and the aqueous phase is extracted twice withdichloromethane. The combined organic phases are washed with 1 Mhydrochloric acid, 1 M NaOH solution, and water. After drying (MgSO₄),the solvent is evaporated under reduced pressure to yield the product asa beige solid.

Yield: 3.0 g (29% of theory)

Mass spectrum (ESI⁺): m/z=204 [M+H]⁺

Example XII

4-Methoxy-9-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene

1 M Borane tetrahydrofuran complex (70 mL) is added dropwise to asolution of4-methoxy-9-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-10-one (3.0 g)in THF (20 mL) chilled in an ice bath. The resulting solution is stirredat reflux temperature for 5 h and then at room temperature overnight.The solution is cooled to ca. −10° C. and half-concentrated hydrochloricacid (50 mL) is added carefully. The mixture is stirred at roomtemperature for 1 h and an additional hour at reflux temperature. Thesolvent is removed and 2 M NaOH solution (50 mL) is added to theresidue. The resulting mixture is extracted with dichloromethane and thecombined organic extracts are dried (MgSO₄). After removal of thesolvent, the residue is taken up in ethanol (20 mL) and the resultingsolution is treated with oxalic acid (3 mL) to obtain the oxalate saltof the title compound.

Yield: 0.8 g (19% of theory)

Mass spectrum (ESI⁺): m/z=190 [M+H]⁺

Example XIII

4-Hydroxy-9-azonia-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene bromide

A solution of 4-methoxy-9-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene(0.50 g, oxalate salt) in hydrobromic acid (48% in water, 10 mL) isstirred at reflux temperature for 3 h. Then, the solution isconcentrated under reduced pressure and the residue is azetropicallydried using toluene and ethanol. The residue is washed with acetone anddried to give the product as a solid.

Yield: 0.23 g (49% of theory)

Mass spectrum (ESI⁺): m/z=176 [M+H]⁺ (of amine)

The following compound is obtained analogously to Example XIII:

(1)(2R,6S)-6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-9-ol

Mass spectrum (ESI⁺): m/z=232 [M+H]⁺

The compound is prepared from(2R,6S)-9-methoxy-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine[tartaric acid salt, for preparation see WO 9959976 (1999)] and isolatedas the hydrogen bromide salt.

Example XIV

9-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

Di-tertbutyl dicarbonate (8.7 g) is added to a solution of6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-9-ol(12.0 g) and triethylamine (8 ml) in dioxane (100 mL) and water (100mL). The solution is stirred at room temperature overnight. Then, ethylacetate is added and the organic phase is separated. The aqueous phaseis extracted with ethyl acetate and the organic extract and phase arecombined. The organic phase is washed with 1 M hydrochloric acid, water,and brine, and then dried (MgSO₄). After removal of the solvent underreduced pressure, the residue is crystallized from diisopropylether togive the title compound.

Yield: 6.5 g (51% of theory)

Mass spectrum (ESI⁺: m/z=332 [M+H]⁺

The following compounds are obtained analogously to Example XIV:

(1)(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

Mass spectrum (ESI⁺): m/z=332 [M+H]⁺

(2)(2R,6R,11S)-8-Hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

(3)(2S,6R)-8-Hydroxy-6,9,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

The compound may be obtained by resolution of the racemic mixture byHPLC on chiral phase.

(4)(2R,6S)-8-Hydroxy-6,9,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

The compound may be obtained by resolution of the racemic mixture byHPLC on chiral phase.

(5)(2S,6R)-9-Hydroxy-6,8,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

The compound may be obtained by resolution of the racemic mixture byHPLC on chiral phase.

(6)(2R,6S)-9-Hydroxy-6,8,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

The compound may be obtained by resolution of the racemic mixture byHPLC on chiral phase.

(7)8-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

(8)(2R,6S)-9-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

Mass spectrum (ESI⁺): m/z=332 [M+H]⁺

The compound may be obtained by resolution of the racemic mixture byHPLC on chiral phase or by using the enantiomerically pure startingmaterial that in turn may be obtained as described in Example XIII(1) orby resolution of the racemic mixture by HPLC on chiral phase. Thesynthesis of the racemic starting material is described in EP 521422(1993).

(9)7-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

Mass spectrum (ESI⁺): m/z=332 [M+H]+

(10)(2R,6S)-8-Acetyl-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

Mass spectrum (ESI⁺): m/z=358 [M+H]⁺

Example XV

Trifluoro-methanesulfonic acid3-(benzothiazole-6-carbonyl)-6-methyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-ylester

Trifluoromethanesulfonic anhydride (0.77 mL) is added to a solution ofbenzothiazol-6-yl-(8-hydroxy-6-methyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone(1.24 g; for synthesis see Example 92), triethylamine (3.4 mL), and4-dimethylaminopyridine (10 mg) in dichloromethane (12 mL) chilled to−10° C. under argon atmosphere. The solution is stirred at ca. −5° C.for 30 min and then at room temperature overnight. The reaction solutionis added to ice-cold water and then concentrated aqueous ammoniasolution is added. The resulting mixture is extracted withdichloromethane, the combined organic extracts are washed with water anddried (MgSO₄). The solvent is removed under reduced pressure to give thecrude product that is used without further purification.

Yield: 1.51 g (89% of theory)

Mass spectrum (ESI⁺): m/z=497 [M+H]⁺

The following compounds are obtained analogously to Example XV:

(1) (2R,6S)-Trifluoro-methanesulfonic acid3-benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-10-ylester

Mass spectrum (ESI⁺: m/z=454 [M+H]⁺

(2)6,11,11-Trimethyl-9-trifluoromethanesulfonyloxy-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

Mass spectrum (ESI⁺): m/z=464 [M+H]⁺

(3)(2R,6S)-6,11,11-Trimethyl-10-trifluoromethanesulfonyloxy-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

Mass spectrum (ESI⁺): m/z=481 [M+NH₄]+

(4)(2R,6R)-6,11-Dimethyl-8-trifluoromethanesulfonyloxy-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

Mass spectrum (ESI⁺): m/z=450 [M+H]⁺

(5)6,11,11-Trimethyl-8-trifluoromethanesulfonyloxy-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

(6)(2R,6S)-6,11,11-Trimethyl-9-trifluoromethanesulfonyloxy-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

Mass spectrum (ESI⁺): m/z=464 [M+H]⁺

(7) (2R,6R,11S)-Trifluoro-methanesulfonic acid9-cyano-6,11-dimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-ylester

Mass spectrum (ESI⁺): m/z=488 [M+NH₄]⁺

(8) (2R,6R,11R)-Trifluoro-methanesulfonic acid9-cyano-6,11-dimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-ylester

Mass spectrum (ESI⁺): m/z=488 [M+NH₄]⁺

(9)6,11,11-Trimethyl-7-trifluoromethanesulfonyloxy-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

Mass spectrum (ESI⁺): m/z=464 [M+H]⁺

(10) Trifluoro-methanesulfonic acid(2R,6R,11S)-6,11-dimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-ylester

Mass spectrum (ESI⁺): m/z=446 [M+H]⁺

Example XVI

(2R,6S)-3-Benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-10-carbonitrile

Tetrakis(triphenylphosphine)palladium(0) (2.79 g) is added to a mixtureof (2R,6S)-trifluoro-methanesulfonic acid3-benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-10-ylester (7.30 g) and zinc cyanide (2.85 g) in dimethylformamide (35 mL)kept in argon atmosphere. The resulting mixture is stirred at 100° C.for 6 h. After cooling to room temperature, water (300 mL), concentratedammonia solution (10 mL), and ethyl acetate (150 mL) are added and theforming precipitate is separated by filtration. The organic layer of thefiltrate is separated and the aqueous layer is extracted twice withethyl acetate. The combined organic phases are washed with brine anddried (MgSO₄). The solvent is removed under reduced pressure and theresidue is purified by chromatography on silica gel (cyclohexane/ethylacetate 19:1) to give the product.

Yield: 4.43 g (62% of theory)

Mass spectrum (ESI⁺: m/z=331 [M+H]⁺

The following compounds are obtained analogously to Example XVI:

(1)(2R,6R,11S)-8-Cyano-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

Mass spectrum (ESI⁺): m/z=327 [M+H]⁺

(2)9-Cyano-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

Mass spectrum (ESI⁺): m/z=341 [M+H]⁺

(3)(2R,6S)-9-Cyano-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

Mass spectrum (ESI⁺): m/z=341 [M+H]⁺

(4)7-Cyano-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

Mass spectrum (ESI⁺): m/z=341 [M+H]⁺

Example XVII

(2R,6S)-3-Benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-10-carboxylicacid ethyl ester

A solution of(2R,6S)-3-benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-10-carbonitrile(1.14 g) in 80% sulfuric acid (4 mL) is stirred at 150° C. for 1 h.After cooling to room temperature, ethanol (30 mL) is added and thesolution is stirred at 100° C. for 2 d. Then, the cooled solution isadded to water (100 mL) and the mixture is basified using 40% aqueousNaOH solution. The resulting mixture is extracted twice with ethylacetate and dried (MgSO₄). The solvent is removed under reduced pressureto give the crude product.

Yield: 1.14 g (87% of theory)

Mass spectrum (ESI⁺): m/z=378 [M+H]⁺

The following compounds are obtained analogously to Example XVII:

(1)6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-carboxylicacid ethyl ester

Mass spectrum (ESI⁺): m/z=288 [M+H]⁺

The compound is prepared from6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-carbonitrileapplying the procedure described above.

(2)(2R,6R,11S)-6,11-Dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-carboxylicacid ethyl ester

Mass spectrum (ESI⁺): m/z=274 [M+H]⁺

The compound is prepared from(2R,6R,11S)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-carbonitrileapplying the procedure described above.

(3)1-Hydroxy-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-2,6-methano-benzo[d]azocine-6-carboxylicacid methyl ester

The compound may be prepared from1-hydroxy-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-2,6-methano-benzo[d]azocine-6-carbonitrile[for synthesis see U.S. Pat. No. 3,687,957 (1972)] as described aboveusing methanol instead of ethanol.

Example XVIII

(2R,6S)-6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-10-carboxylicacid ethyl ester

Pd(OH)₂ (0.20 g) is added to a solution of(2R,6S)-3-benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-10-carboxylicacid ethyl ester (1.13 g) in ethanol (20 mL). The resulting mixture isstirred under hydrogen atmosphere (50 psi) at room temperatureovernight. Then, the catalyst is separated by filtration and thefiltrate is concentrated under reduced pressure to give the product.

Yield: 0.61 g (71% of theory)

Mass spectrum (ESI⁺): m/z=288 [M+H]⁺

The following compounds are obtained analogously to Example XVIII:

(1)(2R,6S)-6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-10-carbonitrile

(2) 2,3,4,5,6,7-Hexahydro-2,6-methano-1H-azocino[5,4-b]indole (racemicmixture of the diastereomer shown)

(3) 5,6,7,8,9,10-Hexahydro-6,10-methano-pyrido[3,2-d]azocine (racemicmixture of the diastereomer shown)

Mass spectrum (ESI⁺): m/z=175 [M+H]⁺

The debenzylation is carried out in the presence of 1 equivalent of 1 Mhydrochloric acid as described above.

(4) 4-Methyl-3,5,9-triaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),4-diene(racemic mixture of the diastereomer shown)

Mass spectrum (ESI⁺): m/z=178 [M+H]⁺

Example XIX

6,11,11-Trimethyl-9-phenyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

Aqueous 2 M Na₂CO₃ solution (5 mL) is added to a mixture of6,11,11-trimethyl-9-trifluoro-methanesulfonyloxy-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester (1.00 g) and phenylboronic acid (0.34 g) indimethylformamide (5 mL) in argon atmosphere. The resulting mixture isflushed with argon and then1,1′-bis(diphenyl-phosphino)ferrocene-palladium(II) dichloridedichloromethane complex (0.18 g) is added. The mixture is heated to 100°C. and stirred at this temperature for 4 h. After cooling to roomtemperature, water is added and the resulting mixture is extracted withethyl acetate. The combined organic extracts are dried (MgSO₄) and thesolvent is removed under reduced pressure. The residue is purified bychromatography on silica gel (cyclohexane/ethyl acetate 9:1->1:1) togive the product as a colorless oil.

Yield: 0.35 g (41% of theory)

Mass spectrum (ESI⁺): m/z=392 [M+H]⁺

The following compounds are obtained in analogy to Example XIX:

(1)(2R,6R,11S)-6,11-Dimethyl-8-phenyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

Mass spectrum (ESI⁺): m/z=378 [M+H]⁺

(2)(2R,6R,11S)-6,11-Dimethyl-8-pyridin-3-yl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

Mass spectrum (ESI⁺): m/z=379 [M+H]⁺

(3)(2R,6R,11S)-6,11-Dimethyl-8-pyridin-4-yl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester

Mass spectrum (ESI⁺): m/z=379 [M+H]⁺

(4)(2R,6R,11S)-6,11-Dimethyl-8-pyrimidin-5-yl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

Mass spectrum (ESI⁺): m/z=380 [M+H]⁺

(5)6,11,11-Trimethyl-7-pyridin-3-yl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

Mass spectrum (ESI⁺): m/z=393 [M+H]⁺

Example XX

6,11,11-Trimethyl-9-phenyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

Trifluoroacetic acid (0.5 mL) is added to a solution of6,11,11-trimethyl-9-phenyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester (0.30 g) in dichloromethane (2.5 mL). The solutionis stirred at ambient temperature for 1 h and is then concentrated underreduced pressure. The crude trifluoroacetic acid salt of the titlecompound is used without further purification.

Yield: 0.31 g (100% of theory)

The following compounds are obtained analogously to Example XX:

(Alternatively, in cases in which the purity of the product isinsufficient after applying the procedure described above the compoundsare purified by HPLC on reversed phase (MeCN/water) to obtain the purecompounds)

(1)(2R,6R,11S)-6,11-Dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-carbonitrile

Mass spectrum (ESI⁺): m/z=227 [M+H]⁺

The compound is obtained as its trifluoroacetic acid salt.

(2)6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-carbonitrile

Mass spectrum (ESI⁺): m/z=241 [M+H]⁺

The compound is obtained as its trifluoroacetic acid salt.

(3)(2R,6S)-6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-10-ylamine

Mass spectrum (ESI⁺): m/z=231 [M+H]⁺

The compound is obtained as its double trifluoroacetic acid salt.

(4)6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-9-ylamine

Mass spectrum (ESI⁺): m/z=231 [M+H]⁺

The compound is obtained as its double trifluoroacetic acid salt.

(5)(2S,6R)-8-Methoxy-6,9,11,11-tetramethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

The compound may be obtained by resolution of the racemic mixture byHPLC on chiral phase or by using the enantiomerically pure(2S,6R)-8-methoxy-6,9,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester.

(6)(2R,6S)-8-Methoxy-6,9,11,11-tetramethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

The compound may be obtained by resolution of the racemic mixture byHPLC on chiral phase or by using the enantiomerically pure(2R,6S)-8-methoxy-6,9,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester.

(7)(2S,6R)-9-Methoxy-6,8,11,11-tetramethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

The compound may be obtained by resolution of the racemic mixture byHPLC on chiral phase or by using the enantiomerically pure(2S,6R)-9-methoxy-6,8,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester.

(8)(2R,6S)-9-Methoxy-6,8,11,11-tetramethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

The compound may be obtained by resolution of the racemic mixture byHPLC on chiral phase or by using the enantiomerically pure(2R,6S)-9-methoxy-6,8,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester.

(9)8,9-Dimethoxy-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

(10)8-Methoxy-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-9-ol

(11)9-Methoxy-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-ol

(12)(2R,6S)-6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-carbonitrile

Mass spectrum (ESI⁺): m/z=241 [M+H]⁺

The compound is obtained as its trifluoroacetic acid salt.

(13)(2S,6R)-9-Methoxy-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

The compound may be obtained from the racemic mixture by separation fromthe enantiomer by HPLC on chiral phase.

(14)(2R,6R,11S)-6,11-Dimethyl-8-phenyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

Mass spectrum (ESI⁺): m/z=278 [M+H]⁺

(15)(2R,6R,11S)-6,11-Dimethyl-8-pyridin-3-yl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

Mass spectrum (ESI⁺): m/z=279 [M+H]⁺

(16)(2R,6R,11S)-6,11-Dimethyl-8-pyridin-4-yl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

Mass spectrum (ESI⁺): m/z=279 [M+H]⁺

(17)(2R,6R,11S)-6,11-Dimethyl-8-pyrimidin-5-yl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

Mass spectrum (ESI⁺): m/z=280 [M+H]⁺

(18)6,11,11-Trimethyl-7-pyridin-3-yl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

Mass spectrum (ESI⁺): m/z=293 [M+H]⁺

(19)6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-7-carbonitrile

Mass spectrum (ESI⁺): m/z=241 [M+H]⁺

(20)(2R,6R,11S)-6,11-Dimethyl-8-(5-methyl-[1,3,4]oxadiazol-2-yl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

Mass spectrum (ESI⁺): m/z=284 [M+H]⁺

The compound is isolated as its trifluoroacetic acid salt.

(21)(2R,6R,11S)-6,11-Dimethyl-8-[1,3,4]oxadiazol-2-yl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

Mass spectrum (ESI⁺): m/z=270 [M+H]⁺

(22)1,1,1-Trifluoro-2-[(2R,6S)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-yl]-propan-2-ol

Mass spectrum (ESI⁺): m/z=328 [M+H]⁺

Example XXI

[(2R,6S)-3-Benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-10-yl]-methanol

A solution of(2R,6S)-3-benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo-[d]azocine-10-carboxylicacid ethyl ester (0.96 g) in tetrahydrofuran (2 mL) is added dropwise toLiAlH₄ (1.6 mL, 2.4 mol/L in THF) in tetrahydrofuran (1.5 mL). Thereaction mixture is stirred at ambient temperature for 90 min. Then,water (4 mL) is added carefully and the resulting mixture is extractedwith ethyl acetate. The combined organic extracts are washed with waterand brine and dried (MgSO₄). The solvent is removed under reducedpressure to give the product.

Yield: 0.62 g (72% of theory)

Mass spectrum (ESI⁺): m/z=336 [M+H]⁺

Example XXII

(2R,6S)-6,10,11,11-Tetramethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

10% Palladium on carbon (0.10 g) is added to a solution of[(2R,6S)-3-benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-10-yl]-methanol(0.60 g) in methanol (10 mL). The mixture is stirred under hydrogenatmosphere (50 psi) at room temperature overnight. Then, another portionof 10% palladium on carbon (0.2 g) and 4 M hydrochloric acid (1 mL) areadded and the mixture is further stirred in hydrogen atmosphere for 4 h.After the catalyst is separated by filtration, the filtrate isconcentrated under reduced pressure to give the hydrochloric acid saltof the title product.

Yield: 0.50 g (100% of theory)

The following compound is obtained analogously to Example XXII:

(1)8-Methoxy-3-methyl-2,3,4,5-tetrahydro-1H-2,6-methano-benzo[d]azocine-6-carboxylicacid methyl ester

The compound may be obtained from1-hydroxy-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-2,6-methano-benzo[d]azocine-6-carboxylicacid methyl ester employing the procedure described above.Alternatively, the reduction may be conducted in analogy to J. Org.Chem. 1987, 52, 5233-5239.

Example XXIII

(2R,6S)-10-Amino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

A flask charged with a stir bar,(2R,6S)-6,11,11-trimethyl-10-trifluoromethanesulfonyloxy-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester (4.0 g), benzhydrylideneamine (3.2 mL), Cs₂CO₃(5.6 g), and toluene (80 mL) is flushed with argon for 10 min. Then,2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (0.35 g) andtris(dibenzylideneacetone)dipalladium (0.18 g) are added and theresulting mixture is stirred at reflux temperature overnight. Aftercooling to room temperature, the reaction mixture is washed with waterand concentrated. The residue is taken up in tetrahydrofuran and 2 Mhydrochloric acid is added. The mixture is stirred at ambienttemperature for 4 h. The precipitate is separated by filtration and thefiltrate is concentrated under reduced pressure. The residue is purifiedby chromatography on silica gel (cyclohexane/ethyl acetate 1:7) to givethe product as a brown oil.

Yield: 0.83 g (29% of theory)

Mass spectrum (ESI⁺: m/z=331 [M+H]⁺

The following compounds are obtained analogously to Example XXIII:

(1)9-Amino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

Mass spectrum (ESI⁺): m/z=331 [M+H]⁺

(2)8-Amino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

Mass spectrum (ESI⁺): m/z=331 [M+H]⁺

Example XXIV

(2R,6S)-10-Fluoro-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

A solution of nitrosonium tetrafluoroborate (0.25 g) in dioxane (2 mL)is added to a solution of(2R,6S)-10-amino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester (0.10 g) in dioxane (2 mL). The solution is heatedto 50° C. and stirred at this temperature overnight. The reactionsolution is diluted with methanol and then concentrated under reducedpressure. The residue is purified by HPLC on reversed phase(MeCN/H₂O/F₃CCO₂H) to yield the title product.

Yield: 25 mg (36% of theory)

Mass spectrum (ESI⁺): m/z=234 [M+H]⁺

The following compounds are obtained analogously to Example XXIV:

(1)8-Fluoro-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

(2)9-Fluoro-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

In cases in which the tert-butyloxycarbonyl group is not completelycleaved off after the reaction the crude product is treated withtrifluoroacetic acid in dichloromethane.

Example XXV

8,9-Dihydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

Di-tert-butyl dicarbonate (0.34 g) is added to a solution of6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8,9-diol(0.44 g) and triethylamine (0.43 mL) in dichloromethane (5 mL). Thesolution is stirred at room temperature for 2 h. Then, the solution iswashed twice with water and once with brine. After drying (MgSO₄), thesolvent is removed under reduced pressure to yield the product.

Yield: 0.43 g (80% of theory)

Mass spectrum (ESI⁻): m/z=346 [M−H]⁻

Example XXVI

8,9-Methylenedioxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

A mixture of8,9-dihydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]-azocine-3-carboxylicacid tert-butyl ester (0.21 g), K₂CO₃ (0.19 g) and diiodomethane (54 μL)in dimethylformamide (5 mL) is heated to 100° C. and stirred at thistemperature for 2 h. Then, another portion of diiodomethane (54 μL) andK₂CO₃ (0.18 g) is added and the mixture is further stirred at 100° C.for 5 h. After cooling to room temperature, water is added and theresulting mixture is extracted with ethyl acetate. The combined organicextracts are washed with brine and dried (MgSO₄). After removal of thesolvent, the residue is purified by chromatography on silica gel(cyclohexane/ethyl acetate 1:1).

Yield: 0.20 g (93% of theory)

Mass spectrum (ESI⁺): m/z=360 [M+H]⁺

Example XXVII

8,9-Methylenedioxy-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

Isopropanolic hydrochloric acid (5 mol/L, 0.55 mL) is added to8,9-methylenedioxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester (0.19 g) dissolved in dichloromethane (2 mL). Theresulting solution is stirred for 2 h at room temperature. Then, thesolution is concentrated under reduced pressure to give the titleproduct as its hydrochloric acid salt.

Yield: 0.15 g (97% of theory)

Mass spectrum (ESI⁺): m/z=260 [M+H]⁺

Example XXVIII

2-(2-Methoxy-benzyl)-3,3-dimethyl-piperidin-4-ol

Sodium borohydride (0.31 g) is added to2-(2-methoxy-benzyl)-3,3-dimethyl-piperidin-4-one (2.00 g, preparedaccording to J. Med. Chem. 2002, 45, 3755-3765 from racemic startingmaterial) dissolved in methanol (20 mL). The solution is stirred for 3 hat room temperature and then 1 M sodium hydroxide solution (40 mL) isadded. After stirring for 10 min, the mixture is extracted withdichloromethane. The combined organic extracts are washed with water anddried (MgSO₄). The solvent is evaporated to give the title product.

Yield: 2.00 g (99% of theory)

Mass spectrum (ESI⁺): m/z=250 [M+H]⁺

Example XXIX

10-Methoxy-11,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

A solution of 2-(2-methoxy-benzyl)-3,3-dimethyl-piperidin-4-ol (0.80 g)in polyphosphoric acid (10 mL) is stirred at 120° C. overnight. Aftercooling the solution to ca. 80° C., water (300 mL) is added and themixture is stirred vigorously for another 10 min. Then, the mixture iscooled in an ice bath, more water is added, and the mixture is basifiedusing 10 M aqueous NaOH. The resulting mixture is extracted with ethylacetate, the combined organic extracts are washed with brine and dried(MgSO₄). The solvent is removed under reduced pressure to yield thetitle product that is used without further purification.

Yield: 0.36 g (49% of theory)

The following compound is obtained analogously to Example XXIX:

(1)(2S,6R)-9-Methoxy-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

The racemic product mixture is resolved into its enantiomers by usingHPLC on chiral phase. The compound may also be obtained in analogy tothe procedure described in J. Med. Chem. 1997, 40, 2922-2930.

Example XXX

4-(2,6-Dimethyl-morpholin-4-ylmethyl)-benzoic acid

Acetic acid (0.34 mL), trimethyl orthoformate (0.66 mL), and sodiumtriacetoxyborohydride (0.53 g) are successively added to4-formyl-benzoic acid (150 mg) and 2,6-dimethyl-morpholine (115 mg)dissolved in dimethylformamide (3 mL). The solution is stirred at roomtemperature overnight. Trifluoroacetic acid (50% in water) is added, thesolution is stirred for another 2 h and then concentrated under reducedpressure. The residue is purified by HPLC on reversed phase (MeCN/H₂O)to give the title compound as its trifluoroacetic acid salt.

Yield: 199 mg (55% of theory)

Mass spectrum (ESI⁺): m/z=250 [M+H]⁺

The following compounds are obtained analogously to Example XXX:

(1) 4-(4-Hydroxy-4-methyl-piperidin-1-ylmethyl)-benzoic acid

Mass spectrum (ESI⁺): m/z=250 [M+H]⁺

The compound is isolated as its trifluoroacetic acid salt

(2) endo-4-(3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-ylmethyl)-benzoic acid

Mass spectrum (ESI⁺): m/z=262 [M+H]⁺

The compound is isolated as its trifluoroacetic acid salt

(3) 4-(3-Hydroxy-azetidin-1-ylmethyl)-benzoic acid

Mass spectrum (ESI⁺): m/z=208 [M+H]⁺

The compound is isolated as its trifluoroacetic acid salt

(4) 4-(3-Hydroxy-pyrrolidin-1-ylmethyl)-benzoic acid

Mass spectrum (ESI⁺): m/z=221 [M+H]⁺

The compound is isolated as its trifluoroacetic acid salt

(5) 4-(4-Methoxy-piperidin-1-ylmethyl)-benzoic acid

Mass spectrum (ESI⁺): m/z=250 [M+H]⁺

The compound is isolated as its trifluoroacetic acid salt

(6) 4-(4-Hydroxy-piperidin-1-ylmethyl)-benzoic acid

Mass spectrum (ESI⁺): m/z=236 [M+H]⁺

The compound is isolated as its trifluoroacetic acid salt

Example XXXI

(2R,6S)-6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

10% Pd/C (0.20 g) is added to a solution of(2R,6S)-trifluoro-methanesulfonic acid3-benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-10-ylester (0.50 g) in ethanol (10 mL). The resulting mixture is shaken underhydrogen atmosphere (50 psi) at room temperature overnight. Then, thecatalyst is separated by filtration and Pd(OH)₂ (0.2 g) is added to thefiltrate (the benzyl group was not completely removed after thetreatment in the presence of Pd/C). The mixture is shaken for another 16h in hydrogen atmosphere (50 psi) at room temperature. The catalyst isseparated and the filtrate is concentrated under reduced pressure togive the crude product that is used without further purification.

Yield: 0.23 g (98% of theory)

The following compound is obtained analogously to Example XXXI:

(1) 3,5,9-Triaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),4-diene (racemicmixture of the diastereomer shown)

Example XXXII

(2R,6S)-2,2,2-Trifluoro-1-(10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-ethanone

Trifluoroacetic anhydride (5.0 mL) is added to a solution of thehydrobromic acid salt of(2R,6S)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-10-ol(5.0 g) and triethylamine (5.5 mL) in dichloromethane (50 mL) chilled inan ice bath. The resulting solution is stirred at ambient temperatureovernight. Then, water is added, the resulting mixture is stirred for anadditional 15 min, and the organic phase is separated. The organic phaseis washed with water and brine, dried (Na₂SO₄), and the solvent isevaporated. The residue is purified by chromatography on silica gel(ethyl acetate/cyclohexane 1:4) to give the product as a foam-likesolid.

Yield: 3.34 g (64% of theory)

Mass spectrum (ESI⁺): m/z=328 [M+H]⁺

The following compounds are obtained analogously to Example XXXII:

(1)(2R,6S)-2,2,2-Trifluoro-1-(6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-ethanone

Mass spectrum (ESI⁺): m/z=312 [M+H]⁺

(2)(2R,6R,11S)-2,2,2-Trifluoro-1-(8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-ethanone

Mass spectrum (ESI⁺): m/z=314 [M+H]⁺

(3)(2R,6R,11R)-2,2,2-Trifluoro-1-(8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-ethanone

Mass spectrum (ESI⁺): m/z=314 [M+H]⁺

(4)(2R,6S)-2,2,2-Trifluoro-1-(9-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-ethanone

Example XXXIII

2,2,2-Trifluoro-1-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-9-nitro-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone

Nitric acid (0.4 mL) is slowly added to a solution of2,2,2-trifluoro-1-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone(2.9 g) in acetic acid (5 mL) chilled in an ice bath. The ice bath isremoved and the solution is stirred at ambient temperature overnight.The solution is poured into ice-cold water and the resulting mixture isextracted with ethyl acetate. The combined extracts are washed withbrine and dried (Na₂SO₄). After removal of the solvent under reducedpressure, the residue is purified by chromatography on silica gel (ethylacetate/cyclohexane 1:9->1:3).

Yield: 1.3 g (39% of theory)

Mass spectrum (ESI⁻): m/z=371 [M−H]⁻

The following compounds are obtained analogously to Example XXXIII:

(1)2,2,2-Trifluoro-1-[(2R,6R,11S)-8-hydroxy-6,11-dimethyl-9-nitro-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone

Mass spectrum (ESI⁺): m/z=359 [M+H]⁺

(2)2,2,2-Trifluoro-1-[(2R,6R,11S)-8-hydroxy-6,11-dimethyl-7-nitro-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone

Mass spectrum (ESI⁺): m/z=359 [M+H]⁺

The compound is obtained in a mixture with compound Example XXXIII(1)that is separated by chromatography as described above.

(3)2,2,2-Trifluoro-1-[(2R,6S)-9-hydroxy-6,11,11-trimethyl-8-nitro-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone

Mass spectrum (ESI⁺): m/z=373 [M+H]⁺

The compound is obtained in a mixture with compound Example XXXIII(4)that is separated by chromatography as described above.

(4)2,2,2-Trifluoro-1-[(2R,6S)-9-hydroxy-6,11,11-trimethyl-10-nitro-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone

Mass spectrum (ESI⁺): m/z=373 [M+H]⁺

The compound is obtained in a mixture with compound Example XXXIII(3)that is separated by chromatography as described above.

Example XXXIV

(2R,6S)-2,2,2-Trifluoro-1-(10-methoxy-6,11,11-trimethyl-9-nitro-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-ethanone

Methyl iodide (80 μL) is added to a mixture of(2R,6S)-2,2,2-trifluoro-1-(10-hydroxy-6,11,11-trimethyl-9-nitro-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-ethanone(0.40 g) and potassium carbonate (0.17 g) in dimethylformamide (5 mL).The mixture is stirred at room temperature overnight, before anotherportion of methyl iodide (80 μL) and potassium carbonate (0.16 g) areadded. The mixture is stirred for another 6 h at room temperature. Then,water and ethyl acetate are added, the organic phase is separated, andthe aqueous phase is extracted with ethyl acetate. The combined organicphases are washed with brine and dried (Na₂SO₄). The solvent isevaporated to give the crude product that is used without furtherpurification.

Yield: 0.41 g (100% of theory)

Mass spectrum (ESI⁺): m/z=387 [M+H]⁺

The following compounds are obtained analogously to Example XXXIV:

(1)(2S,6R)-8-Methoxy-6,9,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

The compound may be obtained by resolution of the racemic mixture byHPLC on chiral phase or by using the enantiomerically pure(2S,6R)-8-hydroxy-6,9,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester.

(2)(2R,6S)-8-Methoxy-6,9,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

The compound may be obtained by resolution of the racemic mixture byHPLC on chiral phase or by using the enantiomerically pure(2R,6S)-8-hydroxy-6,9,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester.

(3)(2S,6R)-9-Methoxy-6,8,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

The compound may be obtained by resolution of the racemic mixture byHPLC on chiral phase or by using the enantiomerically pure(2S,6R)-9-hydroxy-6,8,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester.

(4)(2R,6S)-9-Methoxy-6,8,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

The compound may be obtained by resolution of the racemic mixture byHPLC on chiral phase or by using the enantiomerically pure(2R,6S)-9-hydroxy-6,8,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester.

(5)8,9-Dimethoxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

Twice the amount of methyl iodide and potassium carbonate as describedin the procedure above are employed to prepare the compound from8,9-dihydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester.

(6)9-Hydroxy-8-methoxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

The compound is obtained in a mixture with8-hydroxy-9-methoxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester and8,9-dimethoxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester from8,9-dihydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester that may be separated by HPLC on reversed phase.

(7)8-Hydroxy-9-methoxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

The compound is obtained in a mixture with9-hydroxy-8-methoxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester and8,9-dimethoxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester from8,9-dihydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester that may be separated by HPLC on reversed phase.

(8)9-Methoxy-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

(9)(2S,6R)-9-Methoxy-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

The compound may be obtained from the racemic mixture by HPLC on chiralphase.

(10)2,2,2-Trifluoro-1-[(2R,6R,11S)-8-methoxy-6,11-dimethyl-9-nitro-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone

Mass spectrum (ESI⁺): m/z=373 [M+H]⁺

(11)2,2,2-Trifluoro-1-[(2R,6R,11S)-8-methoxy-6,11-dimethyl-7-nitro-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone

Mass spectrum (ESI⁺): m/z=373 [M+H]⁺

Example XXXV

1-[(2R,6S)-10-Benzylamino-6,11,11-trimethyl-9-nitro-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone

2,2,2-Trifluoro-1-[(2R,6S)-10-methoxy-6,11,11-trimethyl-9-nitro-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone_(0.41g) is combined with benzylamine (0.7 mL) and the resulting mixture isstirred at 70° C. overnight. After cooling to room temperature, themixture is purified by HPLC on reversed phase (MeCN/H₂O/TFA) to give theproduct as an oil.

Yield: 0.19 g (38% of theory)

Mass spectrum (ESI⁺): m/z=462 [M+H]⁺

The following compound is obtained analogously to Example XXXV:

(1)1-[(2R,6R,11S)-8-Benzylamino-6,11-dimethyl-9-nitro-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone

The reaction mixture is stirred at 170° C. for 5 h.

Example XXXVI

(5R,9S)-4,5,6,7,8,9-hexahydro-9,12,12-trimethyl-5,9-methano-1H-imidazo[5,4-i][3]benzazocine

A mixture of Raney-Ni (0.1 g),1-[(2R,6S)-10-benzylamino-6,11,11-trimethyl-9-nitro-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone_(0.19g), and formic acid (10 mL) is stirred in hydrogen atmosphere at 50° C.overnight. Then, the catalyst is separated by filtration and thefiltrate is concentrated. The remainder is taken up in methanol (10 mL)and treated with 4 M NaOH solution (2 mL) at 50° C. overnight. Aftercooling to room temperature, the solution is neutralized with 2 Mhydrochloric acid and the solvent is removed. The residue is purified byHPLC on reversed phase (MeCN/H₂O).

Yield: 35 mg (33% of theory)

The following compound is obtained analogously to Example XXXVI:

(1)(6R,10R,12S)-5,6,7,8,9,10-Hexahydro-10,12-dimethyl-6,10-methano-1H-imidazo[5,4-i][3]benzazocine

Mass spectrum (ESI⁺): m/z=242 [M+H]⁺

Example XXXVII(2R,6S)-6,11,11-Trimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-sulfonylchloride and(2R,6S)-6,11,11-trimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-sulfonylchloride

Chlorosulfonic acid (1.15 mL) is slowly added to a solution of2,2,2-trifluoro-1-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone(0.90 g) in dichloromethane (10 mL) at room temperature. Then, thesolution is stirred at ambient temperature overnight. The solution ispoured into ice-cold water and the resulting mixture is extracted withethyl acetate. The combined organic extracts are washed with brine anddried (MgSO₄). The solvent is removed under reduced pressure to give thecrude title compounds in a mixture that is used without furtherpurification.

Yield: 1.18 g

Example XXXVIII

(2R,6S)-6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-sulfonicacid dimethylamide and(2R,6S)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-sulfonicacid dimethylamide

Dimethylamine (3.3 mL, 2 M in THF) is added to a mixture of(2R,6S)-6,11,11-trimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-sulfonylchloride and(2R,6S)-6,11,11-trimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-sulfonylchloride (0.90 g, crude product from Example XXXVII) dissolved inethanol (5 mL) and chilled in an ice bath. The cooling bath is removedand the solution is stirred at room temperature for 2 h. Then, 4 M NaOHsolution (2.2 mL) is added to cleave off the trifluoroacetyl group.After stirring at room temperature for 1 h, the solution is diluted withwater and the resulting mixture is extracted with ethyl acetate. Thecombined extracts are washed with brine and dried (MgSO₄). The solventis removed and the residue is purified by HPLC on reversed phase(MeCN/H₂O/NH₃) to give the two title compounds separated.

(2R,6S)-6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-sulfonicacid dimethylamide: Yield: 500 mg (71% of theory)

Mass spectrum (ESI⁺): m/z=323 [M+H]⁺

(2R,6S)-6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-sulfonicacid dimethylamide: Yield: 50 mg (7% of theory)

Mass spectrum (ESI⁺): m/z=323 [M+H]⁺

The following compounds are obtained analogously to Example XXXVIII:

(1)(2R,6S)-6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-sulfonicacid methylamide

Mass spectrum (ESI⁺): m/z=309 [M+H]⁺

Methylamine is used as coupling partner.

(2)(2R,6S)-6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-sulfonicacid amide

Mass spectrum (ESI⁺): m/z=295 [M+H]⁺

Ammonia is used as coupling partner.

Example XXXIX

1-[(2R,6S)-8-Acetyl-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanoneand1-[(2R,6S)-9-acetyl-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone

Acetyl chloride (0.25 mL) is added to a suspension of AlCl₃ (1.3 g) indichloromethane (5 mL) chilled in an ice bath. After stirring themixture for 5 min,2,2,2-trifluoro-1-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone(1.0 g) dissolved in dichloromethane (5 mL) is added dropwise. Themixture is stirred at ambient temperature overnight and then poured intoice-cold half-concentrated hydrochloric acid (20 mL). The resultingmixture is extracted with dichloromethane and the combined organicextracts are washed with water, aqueous NaHCO₃ solution, and brine anddried (MgSO₄). The solvent is removed and the residue is purified bychromatography on silica gel (cyclohexane/ethyl acetate 3:1->1:1) togive the two regioisomeric title compounds in a ca. 3:1 mixture.

Yield: 0.83 g (73% of theory)

Mass spectrum (ESI⁺): m/z=354 [M+H]⁺

Example XL

1-[(2R,6S)-6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-yl]-ethanoneand1-[(2R,6S)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-9-yl]-ethanone

4 M NaOH solution (2.5 mL) is added to a ca. 3:1 mixture of1-[(2R,6S)-8-acetyl-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanoneand1-[(2R,6S)-9-acetyl-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone(0.83 g) in methanol (10 mL). The resulting solution is stirred at roomtemperature overnight. Then, the solution is neutralized with 1 Mhydrochloric acid and concentrated. The residue is purified by HPLC onreversed phase (acetonitrile/water/NH₃) to give the two title compoundsseparated.

Yield: 0.35 g of1-[(2R,6S)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-yl]-ethanoneand 0.07 g1-[(2R,6S)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-9-yl]-ethanone(combined 71% of theory)

Mass spectrum (ESI⁺): m/z=258 [M+H]⁺

The following compounds are obtained analogously to Example XL:

(1)(2R,6R,11S)-8-Hydroxy-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-carbonitrile

Mass spectrum (ESI⁺): m/z=243 [M+H]⁺

(2)(2R,6S)-8-Methanesulfonyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

Mass spectrum (ESI⁺): m/z=294 [M+H]⁺

(3)(2R,6S)-10-Methanesulfonyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

Mass spectrum (ESI⁺): m/z=294 [M+H]⁺

(4)(6R,10S)-5,6,7,8,9,10-Hexahydro-2,10,12,12-tetramethyl-6,10-methano-1H-imidazo[5,4-i][3]benzazocine

(5)(6R,10S)-5,6,7,8,9,10-Hexahydro-10,12,12-trimethyl-6,10-methano-1H-imidazo[5,4-i][3]benzazocine

(6)(2R,6R,11S)-6,11-Dimethyl-7-nitro-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-ol

Mass spectrum (ESI⁺): m/z=227 [M+H]⁺

(7)(6R,10S)-5,6,7,8,9,10-Hexahydro-10,12,12-trimethyl-6,10-methano-1H-triazolo[5,4-i][3]benzazocine

Mass spectrum (ESI⁺): m/z=257 [M+H]⁺

(8)(6R,10S)-5,6,7,8,9,10-Hexahydro-10,12,12-trimethyl-2-pyrazin-2-yl-6,10-methano-1H-imidazo[5,4-i][3]benzazocine

Mass spectrum (ESI⁺): m/z=334 [M+H]⁺

(9)(6R,10S)-2-(1-Acetyl-piperidin-4-yl)-5,6,7,8,9,100-hexahydro-10,12,12-trimethyl-6,10-methano-1H-imidazo[5,4-i][3]-benzazocine

(10)(6R,10S)-2-Cyclopropyl-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-6,10-methano-1H-imidazo[5,4-i][3]benzazocine

(11)(6R,10S)-5,6,7,8,9,10-Hexahydro-10,12,12-trimethyl-2-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6,10-methano-1H-imidazo[5,4-i][3]benzazocine

(12)(R10S)-2-tert-Butyl-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-6,10-methano-1H-imidazo[5,4-i][3]benzazocine

(13)(6R,10S)-5,6,7,8,9,10-Hexahydro-10,12,12-trimethyl-2-pyridin-3-yl-6,10-methano-1H-imidazo[5,4-i][3]benzazocine

(14)(6R,10S)-5,6,7,8,9,10-Hexahydro-10,12,12-trimethyl-2-[(S)-tetrahydrofuran-2-yl]-6,10-methano-1H-imidazo[5,4-i][3]benzazocine

Mass spectrum (ESI⁺): m/z=326 [M+H]⁺

(15)(6R,10S)-5,6,7,8,9,10-Hexahydro-10,12,12-trimethyl-2-pyridazin-4-yl-6,10-methano-1H-imidazo[5,4-i][3]benzazocine

(16)(6R,10S)-5,6,7,8,9,10-Hexahydro-10,12,12-trimethyl-2-(5-methyl-pyrazin-2-yl)-6,10-methano-1H-imidazo[5,4-i][3]benzazocine

Mass spectrum (ESI⁺): m/z=348 [M+H]⁺

(17)(6R,10S)-5,6,7,8,9,10-Hexahydro-10,12,12-trimethyl-2-[(R)-tetrahydrofuran-2-yl]-6,10-methano-1H-imidazo[5,4-i][3]benzazocine

Mass spectrum (ESI⁺): m/z=326 [M+H]⁺

(18)(7R,11R,12S)-6,7,8,9,10,11-Hexahydro-2,11,12-trimethyl-6,10-methano-oxazolo[4,5-h][3]benzazocine

Mass spectrum (ESI⁺): m/z=257 [M+H]⁺

(19)(6R,10S)-5,6,7,8,9,10-Hexahydro-2,10,12,12-tetramethyl-6,10-methano-oxazolo[4,5-i][3]benzazocine

(20)(6R,10S)-2-Cyclopropyl-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-6,10-methano-oxazolo[4,5-i][3]benzazocine

(21)(6R,10R,12S)-5,6,7,8,9,10-Hexahydro-2,10,12-trimethyl-6,10-methano-oxazolo[5,4-i][3]benzazocine

Mass spectrum (ESI⁺): m/z=257 [M+H]⁺

(22)(6R,10R,12S)-2-Cyclopropyl-5,6,7,8,9,10-hexahydro-10,12-dimethyl-6,10-methano-oxazolo[5,4-i][3]-benzazocine

(23)(6R,10S)-2-tert-Butyl-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-6,10-methano-oxazolo[4,5-i][3]benzazocine

(24)(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-2-(5-methyl-pyrazin-2-yl)-6,10-methano-oxazolo[4,5-i][3]benzazocine

(25)(6R,10R,12S)-5,6,7,8,9,10-hexahydro-10,12-dimethyl-2-(5-methyl-pyrazin-2-yl)-6,10-methano-oxazolo[5,4-i][3]benzazocine

Mass spectrum (ESI⁺): m/z=335 [M+H]⁺

(26)(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-2-[(R)-tetrahydrofuran-2-yl]-6,10-methano-oxazolo[4,5-i][3]benzazocine

(27)(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-2-[(S)-tetrahydrofuran-2-yl]-6,10-methano-oxazolo[4,5-i][3]benzazocine

Example XLI

1-[(2R,6R,11S)-9-Bromo-8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone

A solution of2,2,2-trifluoro-1-[(2R,6R,11S)-8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone(3.0 g) and pyridinium tribromide (3.3 g) in acetic acid (2 mL) isstirred at 80° C. for 2 h. After cooling to room temperature, water isadded and the resulting mixture is extracted with ethyl acetate. Thecombined organic extracts are washed with water, aqueous NaHCO₃solution, and brine. After drying (Na₂SO₄), the solvent is removed andthe residue is purified by chromatography on silica gel(cyclohexane/ethyl acetate 4:1->1:1).

Yield: 2.5 g (67% of theory)

Mass spectrum (ESI⁺): m/z=392/394 (Br) [M+H]⁺

The following compound is obtained analogously to Example XLI:

(1)1-[(2R,6R,11R)-9-Bromo-8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone

Mass spectrum (ESI⁺): m/z=392/394 (Br) [M+H]⁺

Example XLII

(2R,6R,11S)-8-Hydroxy-6,11-dimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-carbonitrile

A mixture of1-[(2R,6R,11S)-9-bromo-8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone(0.50 g) and copper cyanide (0.23 g) in N-methyl-pyrrolidone (2 mL) isstirred in a microwave oven at 180° C. for 1 h. After cooling to roomtemperature, water is added and the resulting mixture is extracted withethyl acetate. The combined organic extracts are washed with brine anddried (Na₂SO₄). After removing the solvent, the residue is purified bychromatography on silica gel (cyclohexane/ethyl acetate 2:1->1:2).

Yield: 0.20 g (46% of theory)

Mass spectrum (ESI⁺): m/z=339 [M+H]⁺

The following compound is obtained analogously to Example XLII:

(1)(2R,6R,11R)-8-Hydroxy-6,11-dimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-carbonitrile

Mass spectrum (ESI⁺): m/z=339 [M+H]⁺

Example XLIII

(2R,6R,11S)-6,11-Dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-carbonitrile

A solution of KF (76 mg) in water (1 mL) followed bypolymethylhydrosiloxane (1.0 g) is added to a mixture of(2R,6R,11S)-trifluoro-methanesulfonic acid9-cyano-6,11-dimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-ylester (0.30 g) and Pd(OAc)₂ (7 mg) in tetrahydrofuran (3 mL). Theresulting mixture is stirred at room temperature overnight before 1 MNaOH (20 mL) is added. After stirring vigorously for 1 h, the organicphase is separated and the aqueous phase is extracted with ethylacetate. The combined organic phases are washed with water and brine anddried (MgSO₄). The solvent is removed and the residue is taken up in 4 MNaOH (1 mL) and methanol (3 mL) and stirred at room temperatureovernight. Then, the solution is neutralized with 1 M hydrochloric acid,filtered, concentrated and the residue is purified by HPLC on reversedphase (MeCN/water).

Yield: 0.07 g (48% of theory)

Mass spectrum (ESI⁺): m/z=227 [M+H]⁺

The following compound is obtained analogously to Example XLIII:

(1)(2R,6R,11R)-6,11-Dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-carbonitrile

Example XLIV

1-[(2R,6S)-8-Bromo-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanoneand1-[(2R,6S)-10-bromo-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone

AlCl₃ (147 mg) is added to a solution of2,2,2-trifluoro-1-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone(275 mg) in 1,2-dichloroethane (10 mL). The resulting mixture is stirredat ambient temperature for 10 min before bromine (52 μL) is added. Themixture is heated to 50° C. After stirring at 50° C. for 1 h, themixture is cooled to ambient temperature and diluted withdichloromethane (30 mL) and water (10 mL). The resulting mixture isstirred vigorously for 5 min and then 4 M hydrochloric acid (10 mL) isadded. The organic phase is separated and washed with 4 M hydrochloricacid and water and dried (MgSO₄). The solvent is removed under reducedpressure to give the two title compounds in a mixture with a furtherregioisomerically brominated educt.

Yield: 328 mg (95% of theory)

Mass spectrum (ESI⁺): m/z=390/392 (Br) [M+H]⁺

Example XLV

2,2,2-Trifluoro-1-[(2R,6S)-8-methanesulfonyl-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanoneand2,2,2-trifluoro-1-[(2R,6S)-10-methanesulfonyl-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone

MeSO₂Na (0.79 g) is added to a mixture of CuI (1.5 g) and1-[(2R,6S)-8-bromo-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone/1-[(2R,6S)-10-bromo-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone(300 mg, crude product from Example XLIV) in dimethylsulfoxide (6 mL).The resulting mixture is heated to 120° C. and stirred at thistemperature overnight. After cooling to ambient temperature, the mixtureis poured into a solution of concentrated aqueous ammonia (20 mL) andwater (80 mL). The resulting mixture is extracted with ethyl acetate andthe combined organic extracts are washed with 2 M ammonia solution andbrine.

After drying (MgSO₄), the solvent is removed under reduced pressure andthe residue is purified by HPLC on reversed phase (MeCN/water) to givethe two title compounds separated.

2,2,2-Trifluoro-1-[(2R,6S)-8-methanesulfonyl-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone:Yield: 150 mg (50% of theory)

Mass spectrum (ESI⁺): m/z=390 [M+H]⁺

2,2,2-Trifluoro-1-[(2R,6S)-10-methanesulfonyl-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone:Yield: 100 mg (33% of theory)

Mass spectrum (ESI⁺): m/z=390 [M+H]⁺

Example XLVI

2,2,2-Trifluoro-1-[(2R,6S)-6,11,11-trimethyl-8,9-dinitro-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone

Nitric acid (0.16 mL) is added to a solution of trifluoroacetic acid(0.65 mL) in dichloromethane (4 mL) chilled in an ice bath (ca. 0° C.).After stirring for 10 min,2,2,2-trifluoro-1-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone(0.50 g) in dichloromethane (5 mL) is added. The resulting solution isstirred in the cooling bath for 2 h and then at ambient temperatureovernight. The solution is poured into ice-cold water and the resultingmixture is extracted with dichloromethane. The combined organic extractsare washed with aqueous NaHCO₃ solution and dried (MgSO₄). The solventis removed under reduced pressure and the residue is purified bychromatography on silica gel (cyclohexane/ethyl acetate 1:0->9:1).

Yield: 330 mg (51% of theory)

Mass spectrum (ESI⁺): m/z=402 [M+H]⁺

Example XLVII

1-[(2R,6S)-8,9-Diamino-6,1,11-trimethyl-1,2,5,6-tetrahydro-4H-2-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone

A mixture of 10% palladium on carbon (300 mg) and(2R,6S)-2,2,2-trifluoro-1-(6,11,11-trimethyl-8,9-dinitro-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-ethanone(330 mg) in methanol (5 mL) is shaken under hydrogen atmosphere at roomtemperature for 2 h. Then, the catalyst is separated by filtration andthe solvent is removed under reduced pressure to give the crude titlecompound that is used without further purification.

Yield: 260 mg (93% of theory)

Mass spectrum (ESI⁺): m/z=342 [M+H]⁺

The following compounds are obtained analogously to Example XLVII:

(1)1-[(2R,6R,11S)-7-Amino-8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone

Mass spectrum (ESI⁺): m/z=329 [M+H]⁺

(2)1-[(2R,6S)-8-Amino-9-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone

Mass spectrum (ESI⁺): m/z=343 [M+H]⁺

(3)1-[(2R,6R,11S)-9-Amino-8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone

Mass spectrum (ESI⁺): m/z=329 [M+H]⁺

Example XLVIII

(7R,11S)-6,7,8,9,10,11-Hexahydro-11,13,13-trimethyl-7,11-methano-pyrazino[2,3-i][3]benzazocine

Glyoxal (40% in water, 95 μL) is added to(2R,6S)-1-(8,9-diamino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-2,2,2-trifluoro-ethanone(260 mg) dissolved in ethanol (3 mL) and chilled in an ice bath. Thecooling bath is removed and the solution is stirred at ambienttemperature overnight. Then, the solution is concentrated and theresidue is taken up in methanol (1 mL) and treated with 4 M aqueous NaOHsolution (0.38 mL). After stirring at ambient temperature overnight,brine is added and the resulting mixture is extracted with ethylacetate. The combined organic extracts are washed with brine, dried(MgSO₄), and the solvent is removed under reduced pressure to give thecrude title compound that is used without further purification.

Yield: 204 mg

Mass spectrum (ESI⁺): m/z=268 [M+H]⁺

The following compounds are obtained analogously to Example XLVIII:

(1)(7R,11S)-6,7,8,9,10,11-Hexahydro-2,3,11,13,13-pentamethyl-7,11-methano-pyrazino[2,3-i][3]benzazocine

Mass spectrum (ESI⁺): m/z=296 [M+H]⁺

The compound is obtained by using diacetyl according to the proceduredescribed above.

(2)(7R,11S)-6,7,8,9,10,11-Hexahydro-3,11,13,13-tetramethyl-7,11-methano-pyrazino[2,3-i][3]benzazocineand(7R,11S)-6,7,8,9,10,11-hexahydro-2,11,13,13-tetramethyl-7,11-methano-pyrazino[2,3-i][3]benzazocine

Mass spectrum (ESI⁺): m/z=296 [M+H]⁺

The compounds are obtained as a mixture of each other by usingmethylglyoxal.

Example IL

2,2,2-Trifluoro-1-[(6R,10S)-5,6,7,8,9,10-hexahydro-2,10,12,12-tetramethyl-6,10-methano-1H-imidazo[5,4-i][3]benzazocin-7-yl]-ethanone

(2R,6S)-1-(8,9-Diamino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]-azocin-3-yl)-2,2,2-trifluoro-ethanone(600 mg) dissolved in glacial acetic acid is stirred at 130° C. for 3 h.After cooling to ambient temperature, the solution is concentrated underreduced pressure and the residue is taken up in ethyl acetate. Theorganic solution is washed with aqueous K₂CO₃ solution and brine anddried (MgSO₄). The solvent is removed under reduced pressure to give thecrude title compound as a foam-like solid.

Yield: 642 mg

Mass spectrum (ESI⁺): m/z=366 [M+H]⁺

The following compound is obtained analogously to Example IL:

(1)2,2,2-Trifluoro-1-[(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-6,10-methano-1H-imidazo[5,4-i][3]benzazocin-7-yl]-ethanone

Mass spectrum (ESI⁺): m/z=352 [M+H]⁺

The reaction is carried out with formic acid instead of acetic acid.

Example L(6R,10S)-5,6,7,8,9,10-Hexahydro-3,10,12,12-tetramethyl-6,10-methano-imidazo[4,5-i][3]benzazocineand(6R,10S)-5,6,7,8,9,10-hexahydro-1,10,12,12-tetramethyl-6,10-methano-imidazo[5,4-i][3]benzazocine

Methyl iodide (69 μL) is added to a mixture of2,2,2-trifluoro-1-[(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-6,10-methano-1H-imidazo[5,4-i][3]benzazocin-7-yl]-ethanone(300 mg) and K₂CO₃ (118 mg) in dimethylformamide (2 mL). The resultingmixture is stirred at room temperature overnight. Then, water is addedand the mixture is extracted with ethyl acetate. The combined extractsare washed with brine and dried (MgSO₄). The solvent is removed and theresidue is taken up in methanol (3 mL) and treated with 4 M aqueous NaOHsolution (0.5 mL). The solution is stirred at room temperature overnightand then diluted with ethyl acetate. The resulting solution is washedwith water and brine and dried (MgSO₄). The solvent is removed underreduced pressure to give the crude title compounds as a mixture.

Yield: 90 mg (39% of theory)

The following compounds are obtained analogously to Example L:

(1)(6R,10S)-5,6,7,8,9,10-hexahydro-1,2,10,12,12-pentamethyl-6,10-methano-imidazo[5,4-i][3]benzazocine

Mass spectrum (ESI⁺): m/z=284 [M+H]⁺

(2)(6R,10S)-5,6,7,8,9,10-hexahydro-2,3,10,12,12-pentamethyl-6,10-methano-imidazo[4,5-i][3]benzazocine

Mass spectrum (ESI⁺): m/z=284 [M+H]⁺

The two isomeric compounds (1) and (2) were obtained from the samestarting compound and separated by HPLC on reversed phase.

(3) Mixture of(6R,10S)-5,6,7,8,9,10-hexahydro-1,10,12,12-tetramethyl-6,10-methano-triazolo[5,4-i][3]benzazocineand(6R,10S)-5,6,7,8,9,10-hexahydro-3,10,12,12-tetramethyl-6,10-methano-triazolo[4,5-i][3]benzazocine

The compounds are obtained from compound Example LIX after carrying outthe reactions described above.

Example LI

2-Benzyl-2-aza-bicyclo[3.3.1]nonan-6-ol

Diisobutylaluminumhydride (1.5 mol/L in toluene, 21 mL) is added to asolution of acetic acid 2-benzyl-3-oxo-2-aza-bicyclo[3.3.1]non-6-ylester (1.50 g, for synthesis see J. Chem. Soc., Perkin Trans. 1 1999,1157-1162) in toluene (30 mL) cooled to −70° C. The cooling bath isremoved and the solution is stirred at ambient temperature overnight.Then, another portion of diisobutylaluminumhydride (1.5 mol/L intoluene, 20 mL) is added and the solution is stirred for additional 4 hat room temperature. Then, the solution is poured into ice-cold waterand the resulting mixture is extracted with ethyl acetate. The aqueousphase is acidified using 4 M hydrochloric acid and extracted one moretime with ethyl acetate. The combined organic extracts are dried(Na₂SO₄) and the solvent is removed. The residue is purified bychromatography on silica gel (dichloromethane/methanol 1:0->2:1).

Yield: 440 mg (36% of theory)

Mass spectrum (ESI⁺): m/z=232 [M+H]⁺

Example LII

2-Benzyl-2-aza-bicyclo[3.3.1]nonan-6-one

Dess-Martin periodinane (1.30 g) is added to a solution of2-benzyl-2-aza-bicyclo[3.3.1]-nonan-6-ol (0.60 g) in dichloromethane (15mL) chilled in an ice bath. The cooling bath is removed and the solutionis stirred at ambient temperature for 1 h. Then, the solution is dilutedwith dichloromethane and washed with a mixture of aqueous Na₂S₂O₃solution and aqueous NaHCO₃ solution. The solution is dried (Na₂SO₄) andthe solvent is removed. The residue is purified by chromatography onsilica gel (dichloromethane/methanol 1:0->2:1).

Yield: 250 mg (42% of theory)

Mass spectrum (ESI⁺): m/z=230 [M+H]⁺

Example LIII

3-Benzyl-2,3,4,5,6,7-hexahydro-2,6-methano-1H-azocino[5,4-b]indole

A solution of 2-benzyl-2-aza-bicyclo[3.3.1]nonan-6-one in acetic acid(0.24 g) is added to a solution of PhNHNH₂*HCl (173 mg) in acetic acid(4 mL) heated at reflux temperature. After stirring at this temperaturefor 2 h, the solution is cooled to room temperature and aqueous K₂CO₃solution is added. The resulting mixture is extracted with ethylacetate, the combined organic extracts are dried (Na₂SO₄), and thesolvent is removed. The residue is purified by HPLC on reversed phase(MeCN/water).

Yield: 160 mg (49% of theory)

Example LIV

2-Benzyl-1,4,6-trimethyl-1,2-dihydro-pyridine

PhCH₂MgCl (1 M in Et₂O, 180 mL) is added dropwise to a solution of1,2,4-trimethyl-pyridinium iodide (24.3 g) in Et₂O(90 mL) chilled in anice bath. After stirring in the ice bath for 2 h, the solution is pouredinto a mixture of 72% aqueous HClO₄ (40 mL) and crushed ice (ca. 900mL). The resulting mixture is stirred for 1 h and the precipitate formedis separated by filtration. The precipitate is washed with methanol anddried to afford the HClO₄ salt of the title compound.

Yield: 22.6 g (74% of theory)

Mass spectrum (ESI⁺): m/z=214 [M+H]⁺

Example LV

6-Benzyl-1,2,4-trimethyl-1,2,3,6-tetrahydro-pyridine and2-benzyl-1,4,6-trimethyl-1,2,3,6-tetrahydro-pyridine

NaBH₄ (3.8 g) is added portionwise to a solution of2-benzyl-1,4,6-trimethyl-1,2-dihydro-pyridine (22.6 g) in MeOH (65 mL)and NaOH (1 M in water, 200 mL). The resulting mixture is stirred atroom temperature for 20 min and then at 60° C. for 30 min. After coolingto ambient temperature, the mixture is diluted with water (150 mL) andextracted with Et₂O(3×150 mL). The combined organic extracts are dried(Na₂SO₄) and the solvent is removed to give a mixture of the two titlecompounds that is used without further purification for the nextreaction step.

Yield: 11.7 g (76% of theory)

Mass spectrum (ESI⁺): m/z=216 [M+H]⁺

Example LVI

3,4,6-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

A mixture of 6-benzyl-1,2,4-trimethyl-1,2,3,6-tetrahydro-pyridine and2-benzyl-1,4,6-trimethyl-1,2,3,6-tetrahydropyridine (from Example LV,11.7 g) is combined with 48% HBr in water (30 mL) and 33% HBr in aceticacid (20 mL). The mixture is heated to reflux temperature and stirred atthis temperature for 4 d. After cooling to ambient temperature, aqueousammonia (32%, 45 mL) is carefully added and the resulting mixture isextracted with Et₂O (3×50 mL). The combined organic extracts areextracted with 2 M hydrochloric acid (3×50 mL), the combined aqueousextracts are basified using 32% aqueous ammonia (20 mL), and the basicaqueous phase is extracted with Et₂O (3×50 mL). The combined organicextracts are dried (MgSO₄), the solvent is removed, and the residue ispurified by chromatography on silica gel(EtOAc/MeOH/NH₃95:5.0.5->75:25:2.5). The title compound obtainedthereafter is dissolved in iPrOH and treated with HCl in iPrOH toprecipitate the HCl salt of the title compound from the iPrOH solution.

Yield: 1.7 g (15% of theory)

Mass spectrum (ESI⁺): m/z=216 [M+H]⁺

Example LVII

4,6-Dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonitrile(one diastereomer, relative configurations of the substituents given inthe structure drawn above are confirmed by NMR experiments)

3,4,6-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine (fromExample LVI, 1.7 g) dissolved in CH₂Cl₂ (40 mL) is added to a solutionof BrCN (1.17 g) in CH₂Cl₂ (10 mL) chilled in an ice bath. The coolingbath is removed and the mixture is stirred at ambient temperature for 1h and at 45° C. for 2 h. After cooling to ambient temperature, thesolution is washed with water, 2 M hydrochloric acid, and 10% aqueousK₂CO₃ solution. The solution is dried (MgSO₄), the solvent is removed,and the residue is triturated with little acetone to give the titlecompound.

Yield: 0.98 g (54% of theory)

Mass spectrum (ESI⁺): m/z=227 [M+H]⁺

The following compound is obtained in analogy to Example LVII:

(1)5,6-Dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonitrile(racemic mixture of diastereomer shown)

Mass spectrum (ESI⁺): m/z=227 [M+H]⁺

The starting compound,3,5,6-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine, maybe obtained as described in J. Med. Chem. 1971, 14, 565-68.

Example LVIII

3,4,6-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine(racemic mixture of diastereomer shown)

A mixture of4,6-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonitrile(one diastereomer, 925 mg), water (30 mL), and 4 M hydrochloric acid (30mL) is stirred at reflux temperature for 9 h. After cooling to ambienttemperature, the solution is basified using concentrated aqueous ammoniasolution and the resulting mixture is extracted with EtOAc (2×50 mL).The combined organic extracts are washed with brine and dried (MgSO₄).Removal of the solvent under reduced pressure affords the titlecompound.

Yield: 439 mg (53% of theory)

Mass spectrum (ESI⁺): m/z=202 [M+H]⁺

The following compound is obtained in analogy to Example LVIII:

(1) 5,6-Dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine(racemic mixture of diastereomer shown)

Mass spectrum (ESI⁺): m/z=202 [M+H]⁺

Example LIX

2,2,2-Trifluoro-1-[(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-6,10-methano-1H-triazolo[5,4-i][3]benzazocin-7-yl]-ethanone

A solution of NaNO₂ (330 mg) in water (2 mL) is slowly added to a flaskcharged with a stir bar,1-[(2R,6S)-8,9-diamino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone(650 mg), and acetic acid (15 mL) and chilled in an ice bath. Theresulting mixture is stirred in the cooling bath for 2 h and at ambienttemperature for 1 h. Then, the solution is poured into ice-cold waterand the precipitate formed is separated by filtration and dried toafford the title compound that is used without further purification.

Yield: 610 mg (91% of theory)

Mass spectrum (ESI⁺): m/z=353 [M+H]⁺

Example LX

(2R,6R,11S)-6,11-Dimethyl-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

A flask charged with a stir bar,(2R,6R,11S)-6,11-dimethyl-8-trifluoromethanesulfonyloxy-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester (9.90 g), bis(pinacolato)diboron (6.15 g),1,1′-bis(diphenylphosphino)ferrocene (0.73 g), and dioxane (50 mL) isflushed with argon for 15 min. Then,1,1′-bis(diphenylphosphino)-ferrocene-palladium dichloridedichloromethane complex (1.08 g) is added and the mixture is heated to80° C. After stirring at 80° C. for 2 d and cooling to ambienttemperature, the mixture is diluted with tBuOMe (150 mL) and washed withwater (3×100 mL) and brine (1×100 mL). The organic phase is dried(MgSO₄) and the solvent is removed under reduced pressure. The residueis purified by chromatography on silica gel (cyclohexane/ethyl acetate9:1->2:3) to give the title compound as a colorless oil.

Yield: 6.90 g (73% of theory)

Mass spectrum (ESI⁺: m/z=428 [M+H]+

Example LXI

(2R,6R,11S)-6,11-Dimethyl-8-borono-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

A solution of(2R,6R,11S)-6,11-dimethyl-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester (2.50 g) and NaIO₄ (5.00 g) in 1 M aqueous NH₄OAcsolution (34 mL) and acetone (60 mL) is stirred at room temperatureovernight. Then, the solution is concentrated, water is added to theresidue, and the resulting mixture is extracted with ethyl acetate. Thecombined organic extracts are washed with water and brine and dried(Na₂SO₄). The solvent is removed under reduced pressure to give thetitle compound as a colorless, foam-like solid.

Yield: 1.83 g (91% of theory)

Mass spectrum (ESI⁻): m/z=390 [M+HCOO]⁻

Example LXII

(2R,6R,11S)-6,11-Dimethyl-8-(2-methyl-pyrimidin-4-yl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

Pd(OAc)₂ (3.3 mg) is added to a mixture of(2R,6R,11S)-6,11-dimethyl-8-borono-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester (0.30 g), 4-chloro-2-methyl-pyrimidine (93 mg),K₃PO₄ (0.31 g), and2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (11.5 mg) inn-butanol (2 mL) under argon atmosphere. The resulting mixture is heatedto 100° C. and stirred at this temperature overnight. After cooling toroom temperature, ethyl acetate is added, the resulting mixture isfiltered, and the filtrate is concentrated under reduced pressure. Theresidue is taken up in CH₂Cl₂ (3 mL) and treated with F₃CCO₂H (0.5 mL)for 1 h. Then, the solution is concentrated and the residue is purifiedby HPLC on reversed phase (MeCN/H₂O/NH₃) to afford the title compound.

Yield: 0.10 g (48% of theory)

Mass spectrum (ESI⁺): m/z=294 [M+H]⁺

The following compound is obtained in analogy to Example LXII:

(1)(2R,6R,11S)-6,11-Dimethyl-8-pyrimidin-4-yl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

Mass spectrum (ESI⁺): m/z=280 [M+H]⁺

Example LXIII

(2R,6R,11S)-6,11-Dimethyl-8-(6-methyl-pyridazin-3-yl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

2 M Aqueous Na₂CO₃ solution (1.13 mL) is added to a mixture of(2R,6R,11S)-6,11-dimethyl-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester (483 mg) and 3-chloro-6-methyl-pyridazine (218 mg)in dimethylformamide (2 mL). The resulting mixture is flushed with argonand then 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloridedichloromethane complex (73 mg) is added. The mixture is heated to 100°C. and stirred at this temperature overnight. After cooling to roomtemperature, water is added and the resulting mixture is extracted withethyl acetate. The combined organic extracts are washed with water andbrine and dried (MgSO₄). The solvent is removed under reduced pressureand the residue is taken up in CH₂Cl₂ (3 mL) and treated with F₃CCOO₂H(0.5 mL) for 1 h. Then, the solution is concentrated and the residue ispurified by HPLC on reversed phase (MeCN/H₂O/NH₃) to afford the titlecompound.

Yield: 225 mg (68% of theory)

Mass spectrum (ESI⁺): m/z=294 [M+H]⁺

The following compounds are obtained in analogy to Example LXIII:

(1)(2R,6R,11S)-6,11-Dimethyl-8-(1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

Mass spectrum (ESI⁺): m/z=309 [M+H]⁺

Trifluoro-methanesulfonic acid 1-methyl-2-oxo-1,2-dihydro-pyridin-4-ylester or 4-bromo-1-methyl-1H-pyridin-2-one are used as the couplingpartner

(2)5-[(2R,6R,11S)-6,11-Dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-yl]-1-methyl-1H-pyridin-2-one

(3)6-[(2R,6R,11S)-6,11-Dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-yl]-2-methyl-2H-pyridazin-3-one

6-Chloro-2-methyl-2H-pyridazin-3-one is used as the coupling partner.

(4)(2R,6R,11S)-6,11-Dimethyl-8-(2-methyl-pyrimidin-5-yl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

Mass spectrum (ESI⁺): m/z=294 [M+H]⁺

5-Bromo-2-methyl-pyrimidine is used as the coupling partner.

Example LXIV

2,2,2-Trifluoro-1-[(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-2-pyrazin-2-yl-6,10-methano-1H-imidazo[5,4-i][3]benzazocin-7-yl]-ethanone

A solution of pyrazine-2-carboxylic acid (152 mg),2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(397 mg), and triethylamine (0.5 mL) in dimethylformamide (5 mL) isstirred at room temperature for 30 min, before1-[(2R,6S)-8,9-diamino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone(300 mg) is added. The solution is stirred at room temperatureovernight. Then, the solution is diluted with EtOAc and washed withwater and 2 M aqueous K₂CO₃ solution and dried (MgSO₄). The solvent isremoved under reduced pressure and the residue is taken up in aceticacid (5 mL). The resulting solution is heated at 80° C. overnight. Then,the solvent is removed under reduced pressure and the residue isevaporated twice with toluene to give the crude title compound that isused without further purification.

Yield: 380 mg (quantitative)

Mass spectrum (ESI⁺): m/z=430 [M+H]⁺

The following compounds are obtained in analogy to Example LXIV:

(1)1-[(6R,10S)-2-(1-Acetyl-piperidin-4-yl)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-6,10-methano-1H-imidazo[5,4-i][3]benzazocin-7-yl]-2,2,2-trifluoro-ethanone

Mass spectrum (ESI⁺): m/z=477 [M+H]⁺

(2)1-[(6R,10S)-2-Cyclopropyl-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-6,10-methano-1H-imidazo[5,4-i][3]benzazocin-7-yl]-2,2,2-trifluoro-ethanone

(3)2,2,2-Trifluoro-1-[(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-2-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl-6,10-methano-1H-imidazo[5,4-i][3]benzazocin-7-yl]-ethanone

(4)1-[(6R,10S)-2-tert-Butyl-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-6,100-methano-1H-imidazo[5,4-i][3]benzazocin-7-yl]-2,2,2-trifluoro-ethanone

(5)2,2,2-Trifluoro-1-[(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-2-pyridin-3-yl-6,10-methano-1H-imidazo[5,4-i][3]benzazocin-7-yl]-ethanone

(6)2,2,2-Trifluoro-1-{(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-2-[(S)-tetrahydrofuran-2-yl]-6,10-methano-1H-imidazo[5,4-i][3]benzazocin-7-yl}-ethanone

(7)2,2,2-Trifluoro-1-[(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-2-pyridazin-4-yl-6,10-methano-1H-imidazo[5,4-i][3]-benzazocin-7-yl]-ethanone

(8)2,2,2-Trifluoro-1-[(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-2-(5-methyl-pyrazin-2-yl)-6,10-methano-1H-imidazo[5,4-i][3]benzazocin-7-yl]-ethanone

(9)2,2,2-Trifluoro-1-{(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-2-[(R)-tetrahydrofuran-2-yl]-6,10-methano-1H-imidazo[5,4-i][3]benzazocin-7-yl}-ethanone

Mass spectrum (ESI⁺): m/z=422 [M+H]⁺

Example LXV

2,2,2-Trifluoro-1-[(7R,11R,12S)-6,7,8,9,10,11-hexahydro-2,11,12-trimethyl-7,11-methano-1H-oxazolo[4,5-h][3]benzazocin-8-yl]-ethanone

1-[(2R,6R,11S)-7-Amino-8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone(200 mg) taken up in trimethyl orthoacetate (1 mL) is heated at 100° C.for 3 h. After cooling to ambient temperature, the mixture isconcentrated and the residue is triturated with little methanol anddried to give the title compound.

Yield: 100 mg (47% of theory)

Mass spectrum (ESI⁺): m/z=353 [M+H]⁺

The following compounds are obtained in analogy to Example LXV:

(1)2,2,2-Trifluoro-1-[(6R,10S)-5,6,7,8,9,10-hexahydro-2,10,12,12-tetramethyl-6,10-methano-oxazolo[4,5-i][3]benzazocin-7-yl]-ethanone

Mass spectrum (ESI⁺): m/z=367 [M+H]⁺

(2)2,2,2-Trifluoro-1-[(6R,10R,12S)-5,6,7,8,9,10-hexahydro-2,10,12-trimethyl-6,10-methano-oxazolo[5,4-i][3]benzazocin-7-yl]-ethanone

Mass spectrum (ESI⁺): m/z=353 [M+H]⁺

Example LXVI

Cyclopropanecarboxylic acid[(2R,6S)-9-hydroxy-6,11,11-trimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-yl]-amide

Cyclopropylcarbonyl chloride (0.13 mL) is added to a solution of1-[(2R,6S)-8-amino-9-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone(0.50 g) and triethylamine (0.25 mL) in dichloromethane (3 mL). Afterstirring the solution at room temperature overnight, concentratedaqueous ammonia solution (1 mL) and methanol (2 mL) are added and theresulting mixture is stirred for additional 2 h. Then, the solution isconcentrated and water is added to the residue. The resulting mixture isextracted with ethyl acetate and the combined organic extracts arewashed with brine and dried (MgSO₄). The solvent is removed underreduced pressure to give the crude title compound that is used withoutfurther purification.

Yield: 0.62 g (quantitative)

The following compounds are obtained in analogy to Example LXVI:

(1) Cyclopropanecarboxylic acid[(2R,6R,11S)-9-hydroxy-6,11-dimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-yl]-amide

(2) Cyclopropanecarboxylic acid[(2R,6R,11S)-8-hydroxy-6,11-dimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-9-yl]-amide

Mass spectrum (ESI⁺): m/z=397 [M+H]⁺

(3)N-[(2R,6S)-9-Hydroxy-6,11,11-trimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-yl]-2,2-dimethyl-propionamide

(4) 5-Methyl-pyrazine-2-carboxylic acid[(2R,6S)-9-hydroxy-6,11,11-trimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-yl]-amide

Mass spectrum (ESI⁺): m/z=463 [M+H]⁺

Alternatively, the compound is obtained from5-methyl-pyrazine-2-carboxylic acid using2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborateand ethyldiisopropylamine in dimethylformamide as described in ProcedureA.

(5) 5-Methyl-pyrazine-2-carboxylic acid[(2R,6R,11S)-8-hydroxy-6,11-dimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-9-yl]-amide

Mass spectrum (ESI⁺): m/z=449 [M+H]⁺

Alternatively, the compound is obtained from5-methyl-pyrazine-2-carboxylic acid using2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborateand ethyldiisopropylamine in dimethylformamide as described in ProcedureA.

(6) (R)-Tetrahydro-furan-2-carboxylic acid[(2R,6S)-9-hydroxy-6,11,11-trimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-yl]-amide

Preferably, the compound is obtained from(R)-tetrahydro-furan-2-carboxylic acid using2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborateand ethyldiisopropylamine in dimethylformamide as described in ProcedureA.

(7) (S)-Tetrahydro-furan-2-carboxylic acid[(2R,6S)-9-hydroxy-6,11,11-trimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-yl]-amide

Preferably, the compound is obtained from(S)-tetrahydro-furan-2-carboxylic acid using2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborateand ethyldiisopropylamine in dimethylformamide as described in ProcedureA.

Example LXVII

1-[(6R,10S)-2-Cyclopropyl-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-6,10-methano-oxazolo[4,5-i][3]benzazocin-7-yl]-2,2,2-trifluoro-ethanone

A solution of cyclopropanecarboxylic acid[(2R,6S)-9-hydroxy-6,11,11-trimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-yl]-amide(0.62 g) and pyridinium p-toluenesulfonate (76 mg) in xylene (6 mL) isstirred at reflux temperature for 5 h. After cooling to roomtemperature, the solution is concentrated, ethyl acetate is added to theresidue, and the resulting mixture is washed with water and brine. Theorganic solution is dried (MgSO₄) and the solvent is evaporated toafford the title compound.

Yield: 0.52 g (89% of theory)

The following compounds are obtained in analogy to Example LXVII:

(1)1-[(6R,10R,12S)-2-Cyclopropyl-5,6,7,8,9,10-hexahydro-10,12-dimethyl-6,10-methano-oxazolo[4,5-i][3]benzazocin-7-yl]-2,2,2-trifluoro-ethanone

(2)1-[(6R,10R,12S)-2-Cyclopropyl-5,6,7,8,9,10-hexahydro-10,12-dimethyl-6,10-methano-oxazolo[5,4-i][3]benzazocin-7-yl]-2,2,2-trifluoro-ethanone

Mass spectrum (ESI⁺): m/z=379 [M+H]⁺

(3)1-[(6R,10S)-2-tert-Butyl-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-6,10-methano-oxazolo[4,5-i][3]benzazocin-7-yl]-2,2,2-trifluoro-ethanone

(4)2,2,2-Trifluoro-1-[(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-2-(5-methyl-pyrazin-2-yl)-6,1-methano-oxazolo[4,5-i][3]benzazocin-7-yl]-ethanone

(5)2,2,2-Trifluoro-1-[(6R,10R,12S)-5,6,7,8,9,10-hexahydro-10,12-dimethyl-2-(5-methyl-pyrazin-2-yl)-6,1-methano-oxazolo[5,4-i][3]benzazocin-7-yl]-ethanone

(6)2,2,2-Trifluoro-1-[(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-2-[(R)-tetrahydrofuran-2-yl]-6,10-methano-oxazolo[4,5-i][3]benzazocin-7-yl]-ethanone

(7)2,2,2-Trifluoro-1-[(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-2-[(S)-tetrahydrofuran-2-yl]-6,10-methano-oxazolo[4,5-i][3]benzazocin-7-yl]-ethanone

Example LXVIII

6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-7-ol,6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-9-ol,and 3,3,4-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-7-ol

2-(3-Methoxy-benzyl)-3,3-dimethyl-4-methylene-piperidine-1-carbaldehyde(for preparation see J. Med. Chem. 1997, 40, 2928-2939; 47.5 g) iscombined with 48% HBr in water (300 mL). The mixture is heated to refluxtemperature and stirred at this temperature for 24 h. After cooling toambient temperature, the precipitate is separated by filtration, washedwith water, and triturated with acetone. Then, the precipitate is takenup in a mixture of 1 N aqueous NaOH solution and CH₂Cl₂. The CH₂Cl₂phase is separated, dried (Na₂SO₄), and concentrated. The residue isrecrystallized from EtOAc to afford6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-9-ol.The filtrate of the reaction mixture is combined with the water andacetone phases (from washing and triturating the precipitate) andbasified using concentrated aqueous ammonia solution. The resultingmixture is extracted with CH₂Cl₂, the combined organic extracts aredried (MgSO₄), and the solvent is evaporated. The residue is purified bychromatography on silica gel (EtOAc/MeOH/NH₄OH 90:10:1->70:30:3) toafford6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-7-oland 3,3,4-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-7-olseparated.

6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-7-ol

Yield: 5.2 g (13% of theory)

Mass spectrum (ESI⁺): m/z=232 [M+H]⁺

6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-9-ol

Yield: 9.3 g (23% of theory)

Mass spectrum (ESI⁺): m/z=232 [M+H]⁺

3,3,4-Trimethyl-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-7-ol

Yield: 4.2 g (10% of theory)

Mass spectrum (ESI⁺): m/z=232 [M+H]⁺

Example LXIX

(1-Benzyl-allyl)-(2-methyl-allyl)-carbamic acid tert-butyl ester

NaH (60% in mineral oil, 0.15 g) is added to a solution of(1-benzyl-allyl)-carbamic acid tert-butyl ester (for preparation seee.g. Eur. J. Org. Chem. 2002, 1, 139-144; 0.86 g) inN-methylpyrrolidinone (5 mL). The resulting mixture is stirred at roomtemperature for 30 min, before 3-bromo-2-methyl-propene (0.38 mL) isadded. After stirring for 5 h, brine is added and the resulting mixtureis extracted with ethyl acetate. The combined organic extracts are dried(Na₂SO₄), the solvent is evaporated, and the residue is purified bychromatography on silica gel (cyclohexane/ethyl acetate 1:0->1:1).

Yield: 0.79 g (75% of theory)

Mass spectrum (ESI⁺): m/z=302 [M+H]⁺

The following compound is obtained in analogy to Example LXIX:

(1) (1-Benzyl-allyl)-(4-methyl-pent-4-enyl)-carbamic acid tert-butylester

Mass spectrum (ESI⁺): m/z=330 [M+H]⁺

Methanesulfonic acid 4-methyl-pent-4-enyl ester, prepared from4-methyl-pent-4-en-1-ol and mesyl chloride in the presence of NEt₃ indichloromethane, is used as the electrophile.

Example LXX

2-Benzyl-4-methyl-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester

[(1,3-Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]-(phenylmethylene)-(tricyclohexylphosphine)-ruthenium(28 mg) is added to a solution of(1-benzyl-allyl)-(2-methyl-allyl)-carbamic acid tert-butyl ester (0.79g) in toluene (50 mL) under argon atmosphere at room temperature. Theresulting mixture is heated to 60° C. and stirred at this temperaturefor 3 h. After cooling to room temperature, the solvent is evaporatedand the residue is purified by chromatography on silica gel(cyclohexane/ethyl acetate 1:0->1:1).

Yield: 0.40 g (56% of theory)

Mass spectrum (ESI⁺): m/z=274 [M+H]⁺

The following compound is obtained in analogy to Example LXX:

(1) 7-Benzyl-5-methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acidtert-butyl ester

Mass spectrum (ESI⁺): m/z=302 [M+H]⁺

Example LXXI

1-Methyl-10-aza-tricyclo[7.4.1.0*2,7*]tetradeca-2,4,6-triene

Trifluoromethanesulfonic acid (2.5 mL) is added to a solution of7-benzyl-5-methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acidtert-butyl ester (0.30 g) in dichloromethane (5 mL) chilled in an icebath. The ice bath is removed and the solution is stirred at roomtemperature for 5 h. Then, ice-cold water and aqueous K₂CO₃ solution areadded and the resulting mixture is extracted with ethyl acetate. Thecombined extracts are dried (Na₂SO₄), the solvent is evaporated, and theresidue is purified by chromatography on silica gel(dichloroemethane/methanol 99:1->9:1).

Yield: 0.10 g (50% of theory)

Example LXXII

7-Benzyl-6,7,9,10-tetrahydro-5H-6,10-methano-pyrido[3,2-d]azocin-8-one(racemic mixture of diastereomer shown)

A flask charged with a stir bar,2-benzyl-2-aza-bicyclo[3.3.1]nonane-3,6-dione (for preparation see J.Chem. Soc., Perkin Trans. 1, 1999, 1157-1162; 0.80 g), NaAuCl₄.2 H₂O (30mg), propargylamine (0.45 mL), and ethanol (5 mL) is heated at 100° C.with microwave irradiation for 10 min. After cooling to roomtemperature, the mixture is filtered and the filtrate is concentrated.The residue is purified by chromatography on silica gel(cyclohexane/ethyl acetate/methanol 6:4:1).

Yield: 0.52 g (56% of theory)

Example LXXIII

7-Benzyl-5,6,7,8,9,10-hexahydro-6,10-methano-pyrido[3,2-d]azocine(racemic mixture of diastereomer shown)

LiAlH₄ (1 M in THF, 4.5 mL) is added dropwise to a solution of7-benzyl-6,7,9,10-tetrahydro-5H-6,10-methano-pyrido[3,2-d]azocin-8-one(0.55 g) in THF (3 mL) chilled in an ice bath. The cooling bath isremoved and the mixture is stirred at room temperature for 2 h. Ice-coldwater and 4 M hydrochloric acid (4 mL) are added and the mixture isstirred for another 15 min. Then, the mixture is basified using 4 Maqueous NaOH solution and the mixture is extracted with ethyl acetate.The combined organic extracts are dried (Na₂SO₄), the solvent isevaporated, and the residue is purified by chromatography on silica gel(cyclohexane/ethyl acetate/methanol 4:1:0->1:1:1).

Yield: 0.16 g (32% of theory)

The following compounds are obtained in analogy to Example LXXIII:

(1) 9-Benzyl-3,5,9-triaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),4-diene(racemic mixture of diastereomer shown)

Mass spectrum (ESI⁺): m/z=254 [M+H]⁺

(2)9-Benzyl-4-methyl-3,5,9-triaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),4-diene(racemic mixture of diastereomer shown)

Mass spectrum (ESI⁺): m/z=268 [M+H]⁺

Example LXXIV

2-Benzyl-7,7-dibromo-2-aza-bicyclo[3.3.1]nonane-3,6-dione (racemicmixture of diastereomer shown)

A solution of bromine (1.2 mL) in acetic acid (5 mL) is added to asolution of 2-benzyl-2-aza-bicyclo[3.3.1]nonane-3,6-dione (forpreparation see J. Chem. Soc., Perkin Trans. 1, 1999, 1157-1162; 3.05 g)in acetic acid (40 mL). The resulting solution is stirred at roomtemperature for 2 h. Then, the solution is poured into ice-cold waterand the resulting mixture is extracted with ethyl acetate. The combinedorganic extracts are dried (Na₂SO₄) and the solvent is evaporated toafford the title compound as a solid.

Yield: 4.69 g (88% of theory)

Mass spectrum (ESI⁺): m/z=400/402/404 (2 Br) [M+H]⁺

Example LXXV

9-Benzyl-3,5,9-triaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),4-dien-10-one(racemic mixture of diastereomer shown)

A mixture of 2-benzyl-7,7-dibromo-2-aza-bicyclo[3.3.1]nonane-3,6-dione(one diastereomer, 2.50 g), paraforamaldehyde (0.19 g), and ca. 7 Mammonia in methanol (25 mL) is stirred at room temperature overnight.Then, the solution is concentrated and the residue is purified bychromatography on silica gel (CH₂Cl₂/MeOH 99:1->9:1).

Yield: 0.85 g (ca. 85% pure, 44% of theory)

Mass spectrum (ESI⁺): m/z=268 [M+H]⁺

The following compound is obtained in analogy to Example LXXV:

(1)9-Benzyl-4-methyl-3,5,9-triaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),4-dien-10-one(racemic mixture of diastereomer shown)

Acetaldehyde instead of paraformaldehyde is used.

Example LXXVI

(2R,6R,11S)-6,11-Dimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-carboxylicacid methyl ester

2,2,6,6-Tetramethylpiperidine (5.4 mL),1,3-bis(diphenylphosphino)propane (1.30 g), and Pd(OAc)₂ (0.78 g) areadded in turn to a flask charged with trifluoromethanesulfonic acid(2R,6R,11S)-6,11-dimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-ylester (7.0 g), dimethylformamide (30 mL), and methanol (30 mL) in argonatmosphere. The reaction flask is put under CO pressure (7 bar) andshaken at 70° C. for 17 h. After cooling to ambient temperature, wateris added and the resulting mixture is extracted with Et₂O. The combinedorganic extracts are washed with water and brine and dried (MgSO₄). Thesolvent is evaporated to give the title compound as an oil thatcrystallizes while standing.

Yield: 5.2 g (93% of theory)

Mass spectrum (ESI⁺): m/z=356 [M+H]⁺

Example LXXVII

(2R,6R,11S)-6,11-Dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3,8-dicarboxylicacid 3-tert-butyl ester

4 M aqueous NaOH solution (18.5 mL) is added to a solution of(2R,6R,11S)-6,11-dimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-carboxylicacid methyl ester (5.2 g) in methanol (40 mL). The solution is stirredat room temperature overnight. After neutralization of the solution withMeCOOH, NEt₃ (10 mL) and THF (20 mL) are added and the solution iscooled in an ice bath. Then, di-tertbutyl dicarbonate (4.0 g) is added,the cooling bath is removed, and the solution is stirred at ambienttemperature overnight. 1 M aqueous HCl solution (30 mL) is added and theresulting mixture is extracted with ethyl acetate. The combined organicextracts are washed with brine and dried (MgSO₄).

The solvent is evaporated to give the title compound.

Yield: 5.3 g (quantitative)

Mass spectrum (ESI⁺): m/z=346 [M+H]⁺

Example LXXVIII

(2R,6R,11S)-8-Hydrazinocarbonyl-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

NEt₃ (1.7 mL) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (3.9 g) are added in turn to a solution of(2R,6R,11S)-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3,8-dicarboxylicacid 3-tertbutyl ester (4.2 g) in dimethylformamide (10 mL). Theresulting solution is stirred at ambient temperature for 30 min, beforehydrazine hydrate (3 mL) is added. The solution is stirred further atroom temperature for 1 h and then water (30 mL) is added. The resultingmixture is extracted with ethyl acetate and the combined organicextracts are washed with 1 M aqueous NaOH solution, water, and brine.After drying (MgSO₄), the solvent is evaporated and the residue ispurified by chromatography on silica gel (cyclohexane/EtOAc 1:4->0:1) togive the title compound.

Yield: 2.8 g (64% of theory)

Mass spectrum (ESI⁻): m/z=358 [M−H]⁻

Example LXXIX

(2R,6R,11S)-6,11-Dimethyl-8-(5-methyl-[1,3,4]oxadiazol-2-yl)-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

(2R,6R,11S)-8-Hydrazinocarbonyl-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester (0.50 g) in (EtO)₃CMe (2 mL) is heated in amicrowave oven at 120° C. for 30 min. After cooling to room temperature,the mixture is concentrated under reduced pressure and the residue ispurified by HPLC on reversed phase (MeCN/H₂O/NH₄OH) to give the titlecompound.

Yield: 93 mg (17% of theory)

Mass spectrum (ESI⁺): m/z=384 [M+H]⁺

The following compound is obtained in analogy to Example LXXIX:

(1)(2R,6R,11S)-6,11-Dimethyl-8-[1,3,4]oxadiazol-2-yl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

Mass spectrum (ESI⁺): m/z=370 [M+H]⁺

The reaction is conducted at 145° C. with (EtO)₃CH.

Example LXXX

(2R,6R,11S)-8-(4,5-Dimethyl-4H-[1,2,4]triazol-3-yl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

Oxalylic chloride (0.12 mL) is added to a solution N-methylacetamide(102 mg) and 2,6-lutidine (0.33 mL) in dichloromethane (5 mL) chilled inan ice bath. After stirring the solution for 15 min,(2R,6R,11S)-8-hydrazinocarbonyl-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester (0.50 g) is added and the cooling bath is removed.The resulting solution is stirred at ambient temperature for 1 h andthen neutralized with aqueous NaHCO₃ solution. The resulting mixture isextracted with dichloromethane, the combined organic extracts are dried(MgSO₄), and the solvent is evaporated. The residue is taken up inacetic acid (3 mL) and stirred at 120° C. for 2.5 h. After cooling toroom temperature, the mixture is concentrated under reduced pressure andthe residue is taken up in trifluoroacetic acid (1 mL) anddichloromethane (5 mL) to cleave off the tert-butoxycarbonyl group. Thesolution is stirred at room temperature overnight and then concentrated.The residue is dissolved in little methanol/acetonitrile, neutralizedwith aqueous ammonia, and purified by HPLC on reversed phase(MeCN/H₂O/NH₄OH) to give the title compound.

Yield: 50 mg (12% of theory)

Mass spectrum (ESI⁺): m/z=297 [M+H]⁺

Example LXXXI

2-[(2R,6R,11S)-6,11-Dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-yl]-propan-2-oland(2R,6R,11S)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-carboxylicacid methyl ester

MeMgBr (1.4 mol/L in tetrahydrofuran/toluene, 2.0 mL) is added to asolution of(2R,6R,11S)-6,11-dimethyl-3-(2,2,2-trifluoro-acetyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-carboxylicacid methyl ester (0.20 g) in tetrahydrofuran (5 mL) chilled in an icebath. The solution is stirred with cooling for 2 h, before aqueous NH₄Clsolution is added carefully. The resulting mixture is extracted withethyl acetate and the combined organic extracts are washed with brineand dried (MgSO₄). The solvent is evaporated to yield a mixture of thetitle compounds (ca. 4:1 in favor of2-[(2R,6R,11S)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-yl]-propan-2-ol).

Yield: 0.15 g

Mass spectrum (ESI⁺): m/z=260 [M+H] for both compounds determined withanalytical HPLC-MS

Example LXXXII

(2R,6S)-6,11,11-Trimethyl-8-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester

Me₃SiCF₃ (2 M in tetrahydrofuran, 0.42 mL) is added dropwise to amixture of(2R,6S)-8-acetyl-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylicacid tert-butyl ester (0.30 g) and CsF (13 mg) in tetrahydrofuran (3 mL)cooled to ca. −5° C. The mixture is stirred at −5° C. for 1.5 h. Then, 1M aqueous HCl solution (70 mL) is added and the mixture is stirred for 1h. The mixture is basified using aqueous K₂CO₃ solution and thenextracted with ethyl acetate. The combined organic extracts are washedwith brine and dried (MgSO₄). The solvent is evaporated to give thecrude title compound that is submitted for cleaving the protective groupwithout further purification.

Yield: 0.36 g (crude)

Example LXXXIII

1-(3-Bromo-propyl)-2-oxo-indan-1-carboxylic acid methyl ester

A solution of 2-oxo-indan-1-carboxylic acid methyl ester (3.8 g) andNaOH (1 M in water, 20 mL) in ethanol (30 mL) is added dropwise to asolution of 1,3-dibromopropane (10 mL) in ethanol (20 mL) at roomtemperature. The solution is warmed to 40° C. and stirred at thistemperature for 2 d. Then, the solution is concentrated under reducedpressure and ethyl acetate is added to the residue. The resultingmixture is washed with water and brine and dried (MgSO₄). After removingthe solvent, the residue is purified by chromatography on silica gel(cyclohexane/ethyl acetate 20:1->9:1) to give the title compound as anoil.

Yield: 2.1 g (33% of theory)

Mass spectrum (ESI⁺): m/z=311/313 (Br) [M+H]⁺

Example LXXXIV

1,2,3,4,9,9a-Hexahydro-indeno[2,1-b]pyridine-4-a-carboxylic acid methylester

NaN₃ (0.44 g) is added to a solution of1-(3-bromo-propyl)-2-oxo-indan-1-carboxylic acid methyl ester (2.06 g)in dimethylformamide (10 mL) at room temperature. The solution isstirred at room temperature for 4 h and then tBuOMe and ethyl acetateare added. The resulting mixture is washed with water and brine anddried (MgSO₄). Most of the organic solvent is evaporated andtetrahydrofuran (10 mL), acetic acid (0.5 mL), and finally 10% Pd/C (150mg) are added to the residue. The resulting mixture is shaken inhydrogen atmosphere (1 bar) at room temperature for 14 h. Then, themixture is filtered, the filtrate is concentrated, and the residue istaken up in tBuOMe. The organic phase is washed with aqueous Na₂CO₃solution and brine and dried (MgSO₄). Then, the solvent is evaporatedand the residue is dissolved in methanol (10 mL). To the solution isadded acetic acid (0.5 mL) and 10% Pd/C (50 mg) and the resultingmixture is shaken under hydrogen atmosphere (1 bar) at room temperaturefor 6 h. Then, the mixture is filtered and the filtrate is concentratedunder reduced pressure to give the crude title compound that is usedwithout further purification.

Yield: 0.44 g (crude)

Preparation of the End Compounds:

Procedure A (Described for Example 1, Table 3)

[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-phenyl-methanone

2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(155 mg; alternatively,N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate may be used) is added to a solution of benzoic acid(60 mg) and ethyldiisopropylamine (0.25 mL) in dichloromethane (1 mL;DMF may be used as well). The resulting solution is stirred at ambienttemperature for 15 min before it is cooled in an ice bath.(2R,6S)-6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-10-ol(0.10 g) is added and the solution is warmed to room temperature andstirred overnight. The mixture is concentrated under reduced pressureand the residue is purified by HPLC on reversed phase (H₂O/MeCN) to givethe product as a beige solid.

Yield: 55 mg (51% of theory)

Mass spectrum (ESI⁺): m/z=336 [M+H]⁺

Procedure B (Described for Example 151, Table 3)

(2R,6R,11S)-3-(3H-Benzoimidazole-5-carbonyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-carboxylicacid

Aqueous 4 M NaOH solution (1 mL) is added to a solution of(2R,6R,11S)-3-(3H-benzoimidazole-5-carbonyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-carboxylicacid ethyl ester (0.60 g) in ethanol (3 mL). The resulting solution isstirred at ambient temperature for 3 h. Then, the solution is slightlyacidified (pH ca. 5) using 1 M hydrochloric acid and the resultingsolution is extracted with ethyl acetate. The combined organic extractsare washed with brine and dried (MgSO₄). The solvent is evaporated underreduced pressure to give the product as a white solid.

Yield: 0.38 g (68% of theory)

Mass spectrum (ESI⁺): m/z=390 [M+H]⁺

Procedure C (Described for Example 155, Table 3)

(2R,6R,11S)-3-(3H-Benzoimidazole-5-carbonyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-carboxylicacid dimethylamide

2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(90 mg) is added to a solution of(2R,6R,11S)-3-(3H-benzoimidazole-5-carbonyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-carboxylicacid benzoic acid (0.10 g) and ethyldiisopropylamin (53 μL) indimethylformamide (2 mL). The resulting solution is stirred at ambienttemperature for 20 min before dimethylamine (40% in H₂O, 60 μL) isadded. The solution is stirred overnight. The mixture is concentratedunder reduced pressure and the residue is purified by HPLC on reversedphase (H₂O/MeCN/NH₃) to give the product as a solid.

Yield: 55 mg (51% of theory)

Mass spectrum (ESI⁺): m/z=417 [M+H]⁺

Procedure D (Described for Example 172, Table 3)

[(2R,6R,11S)-8-Aminomethyl-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(3H-benzoimidazol-5-yl)-methanone

A solution of(2R,6R,11S)-3-(3H-benzoimidazole-5-carbonyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-carbonitrile(50 mg) in 1 M ammonia in methanol (5 mL) is treated with Raney Ni (50mg) under hydrogen atmosphere at 50° C. for 3 h. Then, the catalyst isseparated by filtration and the filtrate is concentrated under reducedpressure.

The residue is purified by HPLC on reversed phase (H₂O/MeCN) to give theproduct as a white foam-like solid.

Yield: 20 mg (33% of theory)

Mass spectrum (ESI⁺): m/z=375 [M+H]⁺

Procedure E (Described for Example 174, Table 3)

Benzothiazol-6-yl-(6-methyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone

Palladiumdiacetate (10 mg), triethylamine (0.25 mL), formic acid (93μL), and triphenylphosphine (16 mg) are added in turn to a solution oftrifluoro-methanesulfonic acid3-(benzothiazole-6-carbonyl)-6-methyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-ylester (0.30 g) in dimethylformamide (1 mL) under argon atmosphere. Theresulting mixture is stirred at 60° C. for 20 h. After cooling to roomtemperature, brine is added and the resulting mixture is extracted threetimes with ethyl acetate. The combined organic extracts are washed withbrine and dried (Na₂SO₄). The solvent is evaporated under reducedpressure and the residue is purified by HPLC on reversed phase(H₂O/MeCN).

Yield: 46 mg (22% of theory)

Mass spectrum (ESI⁺): m/z=349 [M+H]⁺

Procedure F (Described for Example 175, Table 3)

3-(1H-Benzoimidazole-5-carbonyl)-N-hydroxy-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-carboxamidine

A solution of3-(1H-benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-carbonitrile(0.30 g) and hydroxylamine (50% in water, 0.5 ml) in ethanol (5 mL) isstirred at reflux temperature for 2 h. After cooling to roomtemperature, the mixture is concentrated under reduced pressure to givethe title compound as a white foam-like solid.

Yield: 0.32 g (98% of theory)

Mass spectrum (ESI⁺): m/z=418 [M+H]⁺

Procedure G (Described for Example 176, Table 3)

(1H-Benzoimidazol-5-yl)-[6,11,11-trimethyl-9-(5-methyl-[1,2,4]oxadiazol-3-yl)-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone

Acetic anhydride (0.1 mL) is added to a solution of3-(1H-benzoimidazole-5-carbonyl)-N-hydroxy-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-carboxamidine(0.15 g) in 2,4,6-trimethylpyridine (2 mL). The resulting solution isstirred at ambient temperature for 1 h and then at 120° C. for 3 h.After cooling to room temperature, the mixture is concentrated underreduced pressure and the residue is taken up in methanol (10 mL).Concentrated aqueous ammonia solution (1 mL) is added and the solutionis stirred at ambient temperature for 1 h. The solution is concentratedunder reduced pressure and the residue is purified by HPLC on reversedphase (water/MeCN) to give the title compound as a white foam-likesolid.

Yield: 0.15 g (95% of theory)

Mass spectrum (ESI⁺): m/z=442 [M+H]⁺

Procedure H (described for Example 177, Table 3)

3-(Benzothiazole-6-carbonyl)-8-hydroxy-2,3,4,5-tetrahydro-1H-2,6-methano-benzo[d]azocine-6-carbonitrile

Trifluoroacetic anhydride (43 μL) is added to a solution of3-(benzothiazole-6-carbonyl)-8-hydroxy-2,3,4,5-tetrahydro-1H-2,6-methano-benzo[d]azocine-6-carboxylicacid amide (40 mg) and ethyldiisopropylamine (50 μL) in dichloromethane(0.5 mL) chilled in an ice bath. The ice bath is removed and thesolution is stirred at ambient temperature for 4 h. Then, anotherportion of trifluoroacetic anhydride (43 μL) and ethyldiisopropylamine(50 μL) are added and the solution is stirred overnight. Methanol (1 mL)is added and the solution is stirred for another 10 min. The solution isconcentrated under reduced pressure and the residue is purified by HPLCon reversed phase (water/MeCN) to give the title compound.

Yield: 18 mg (47% of theory)

Mass spectrum (ESI⁺): m/z=476 [M+H]⁺

Procedure I (Described for Example 178, Table 3)

N-[3-(3H-Benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-9-ylmethyl]-acetamide

Triethylamine (38 μL) and acetic anhydride (26 μL) are added to asuspension of(9-aminomethyl-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-(3H-benzoimidazol-5-yl)-methanone(0.10 g) in acetonitrile (2 mL). The resulting mixture is stirred atambient temperature for 1 h. Then, methanol (1 mL) and concentratedaqueous ammonia solution (0.5 mL) are added and the resulting solutionis stirred for another 30 min. The solution is concentrated underreduced pressure and the residue is purified by HPLC on reversed phase(water/MeCN) to give the title compound as a white foam-like solid.

Yield: 73 mg (66% of theory)

Mass spectrum (ESI⁺): m/z=431 [M+H]⁺

Procedure J (Described for Example 180, Table 3)

[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(2-methyl-furan-3-yl)-methanone

Boron tribromide (2 mL) is added to a solution of[(2R,6S)-10-methoxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(2-methyl-furan-3-yl)-methanone(0.22 g) in dichloromethane (10 mL). The resulting solution is stirredat ambient temperature for 2 h. Then, water is added and the mixture isstirred for another 10 min. The organic phase is separated and theaqueous phase is extracted with dichloromethane. The combined organicphases are washed with brine and dried (Na₂SO₄). The solvent isevaporated to give the title compound.

Yield: 0.20 g (96% of theory)

Mass spectrum (ESI⁺): m/z=340 [M+H]⁺

Procedure K (Described for Example 181, Table 3)

N-[3-(3H-Benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-9-yl]-methanesulfonamide

Triethylamine (38 μL) and methanesulfonyl chloride (21 μL) are added toa suspension ofN-[3-(3H-benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-9-yl]-methanesulfonamide(50 mg) in acetonitrile (1 mL). After 1 h the reaction is completedelivering the title product additionally sulfonylated at one imidazolenitrogen. Methanol (1 mL) and concentrated aqueous ammonia solution (0.5mL) are added and the mixture is stirred at room temperature overnightand then at 45° C. for another 4 h. The reaction mixture is concentratedunder reduced pressure and the residue is purified by HPLC on reversedphase (water/MeCN/NH₃) to give the title compound as a white foam-likesolid.

Yield: 20 mg (33% of theory)

Mass spectrum (ESI⁺): m/z=453 [M+H]⁺

Procedure L (Described for Example 183, Table 3)

(3H-Benzoimidazol-5-yl)-(10-hydroxy-11,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone

A solution of(3H-benzoimidazol-5-yl)-(10-methoxy-11,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone(0.10 g) in hydrobromic acid (2 mL, 48% in water) is stirred at 80° C.for 24 h. After cooling to ambient temperature, the solution isconcentrated under reduced pressure and the residue is purified by HPLCon reversed phase (MeCN/H₂O/NH₃).

Yield: 0.03 g (30% of theory)

Mass spectrum (ESI⁺): m/z=362 [M+H]⁺

Procedure M (Described for Example 83, Table 3)

(3H-Benzoimidazol-5-yl)-[(2S,6R,11R)-1,8-dihydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone

Sodium borohydride (50 mg) is added to a solution of(2S,6R,11R)-3-(3H-benzoimidazole-5-carbonyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2H-2,6-methano-benzo[d]azocin-1-one(50 g) in ethanol (3 mL). The resulting mixture is stirred at ambienttemperature overnight. Then, the solution is cooled in an ice bath and 1M hydrochloric acid (0.5 mL) is added. After stirring for 5 min, theresulting mixture is concentrated and the residue is purified by HPLC onreversed phase (MeCN/H₂O/NH₃).

Yield: 15 mg (30% of theory)

Mass spectrum (ESI⁺): m/z=378 [M+H]⁺

Procedure N (Described for Example 228, Table 3)

(3H-Benzoimidazol-5-yl)-[(2R,6R,11S)-6,11-dimethyl-8-(1H-tetrazol-5-yl)-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone

A mixture of sodium azide (105 mg), NH₄Cl (87 mg), and(2R,6R,11S)-3-(3H-benzoimidazole-5-carbonyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-carbonitrile(0.30 g) in dimethylformamide (3 mL) is stirred at 100° C. overnight.Then, another portion of NaN₃ (50 mg) and NH₄Cl (40 mg) is added and themixture is stirred at 110° C. for additional 14 h. After cooling toambient temperature, the mixture is diluted with water and MeCN andpurified by HPLC on reversed phase (MeCN/H₂O/NH₃).

Yield: 0.24 g (72% of theory)

Mass spectrum (ESI⁺): m/z=414 [M+H]⁺

Procedure O (Described for Example 229, Table 3)

(3H-Benzoimidazol-5-yl)-[(2R,6S)-8-(1-hydroxy-1-methyl-ethyl)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone

A solution of1-[(2R,6S)-3-(3H-benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-yl]-ethanone(0.10 g) in tetrahydrofuran (1 mL) is added to a solution of MeMgI (3mol/L in Et₂O, 0.25 mL) in tetrahydrofuran (1 mL) chilled in an ice bath(ca. 0° C.). Then, the cooling bath is removed and the solution isstirred at room temperature. After 5 h of stirring, more MeMgI (3 mol/Lin Et₂O, 0.25 mL) is added and the solution is stirred at 50° C. for 4h. After cooling in an ice bath, aqueous NH₄Cl solution is added and theresulting mixture is extracted with ethyl acetate. The combined organicextracts are dried (MgSO₄) and the solvent is removed under reducedpressure. The residue is purified by HPLC on reversed phase (MeCN/H₂O).

Yield: 26 mg (25% of theory)

Mass spectrum (ESI⁺): m/z=418 [M+H]⁺

Procedure P (Described for Example 232, Table 3)

(1H-Benzoimidazol-5-yl)-[(2R,6R,11S)-6,11-dimethyl-8-[1,2,4]oxadiazol-3-yl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone

A mixture of triethyl orthoformate (4 mL) and(2R,6R,11S)-3-(1H-benzoimidazole-5-carbonyl)-N-hydroxy-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-carboxamidine(0.25 g) is stirred at 100° C. for 6 h. After cooling to roomtemperature, the mixture is concentrated and the residue is purified byHPLC on reversed phase (water/MeCN/NH₃) to give the title compound as awhite solid.

Yield: 0.15 g (59% of theory)

Mass spectrum (ESI⁺): m/z=414 [M+H]⁺

Procedure Q (Described for Example 267, Table 3)

[(2R,6R,11S)-7-Amino-8-methoxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(3H-benzoimidazol-5-yl)-methanone

A mixture of 10% palladium on carbon (1.0 g) and(3H-benzoimidazol-5-yl)-[(2R,6R,11S)-8-methoxy-6,11-dimethyl-7-nitro-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone(1.50 g) in methanol (20 mL) is shaken under hydrogen atmosphere at roomtemperature for 1 d. Then, the mixture is filtered and the filtrate isconcentrated under reduced pressure to give the title compound as afoam-like solid.

Yield: 1.25 g (90% of theory)

Mass spectrum (ESI⁺): m/z=391 [M+H]⁺

Procedure R (Described for Example 270, Table 3)

(3H-Benzoimidazol-5-yl)-[(2R,6R,11S)-8-methoxy-6,11-dimethyl-7-pyrrol-1-yl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone

A solution of[(2R,6R,11S)-7-amino-8-methoxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(3H-benzoimidazol-5-yl)-methanone(150 mg) and 2,5-dimethoxy-tetrahydrofuran (50 μL) in acetic acid (2 mL)is stirred at 110° C. for 3 h. After cooling to ambient temperature, thesolution is diluted with water and extracted with ethyl acetate. Thecombined organic extracts are washed with brine and dried (MgSO₄). Then,the solvent is removed to afford the title compound as a foam-likesolid.

Yield: 73 mg (43% of theory)

Mass spectrum (ESI⁺): m/z=441 [M+H]⁺

TABLE 3 Prepared in Example analogy to No. ChemicalName/Structure/Remarks Procedure Characterization 1[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-phenyl-methanone 

A Mass spectrum (ESI⁺): m/z =336 [M + H]⁺ 2(2-Chloro-phenyl)-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]- methanone  

A Mass spectrum (ESI⁺): m/z = 370/372 (Cl) [M + H]⁺ 3 4-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl- 1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]benzamide  

A Mass spectrum (ESI⁺): m/z = 379 [M + H]⁺ 4(3H-Benzoimidazol-5-yl)-[(2R,6S)-10- hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 376 [M + H]⁺ 5[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-o-tolyl-methanone  

A Mass spectrum (ESI⁺): m/z = 350 [M + H]⁺ 6[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-(2-methoxy-phenyl]- methanone  

A Mass spectrum (ESI⁺): m/z = 366 [M + H]⁺ 7[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-m-tolyl-methanone  

A Mass spectrum (ESI⁺): m/z = 350 [M + H]⁺ 82-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]-benzonitrile  

A Mass spectrum (ESI⁺): m/z = 361 [M + H]⁺ 9N-{3-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocine-3-carbonyl]-phenyl}-acetamide  

A Mass spectrum (ESI⁺): m/z = 393 [M + H]⁺ 103-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]-benzonitrile  

A Mass spectrum (ESI⁺): m/z = 361 [M + H]⁺ 11[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(3-methoxy-phenyl)- methanone  

A Mass spectrum (ESI⁺): m/z = 366 [M + H]⁺ 12[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-p-tolyl-methanone  

A Mass spectrum (ESI⁺): m/z = 350 [M + H]⁺ 134-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2(6-methano-benzo[d]azocine-3-carbonyl]-benzonitrile  

A Mass spectrum (ESI⁺): m/z = 361 [M + H]⁺ 14[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(4-methoxy-phenyl)- methanone  

A Mass spectrum (ESI⁺): m/z = 366 [M + H]⁺ 15N-{4-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocine-3-carbonyl]-phenyl}-acetamide  

A Mass spectrum (ESI⁺): m/z = 393 [M + H]⁺ 16[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-[4-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-phenyl]-methanone  

A Mass spectrum (ESI⁺): m/z = 448 [M + H]⁺ 17[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-(2-methyl-3H-benzoimidazol-5-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 390 [M + H]⁺ 18(1H-Benzoimidazol-4-yl)-[(2R,6S)-10- hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 376 [M + H]⁺ 19[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-(1-methyl-1H-benzoimidazol-5-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 390 [M + H]⁺ 20(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 394 [M + H]⁺ 21(3H-Benzotriazol-5-yl)-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 377 [M + H]⁺ 22[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(4-piperidin-1-ylmethyl- phenyl)-methanone  

A Mass spectrum (ESI⁺): m/z = 433 [M + H]⁺ 23[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-methanone  

A Mass spectrum (ESI⁺): m/z = 448 [M + H]⁺ 24[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-(4-morpholin-4-ylmethyl-phenyl)-methanone  

A Mass spectrum (ESI⁺): m/z = 435 [M + H]⁺ 25[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(4-morpholin-4-yl- phenyl)-methanone  

A Mass spectrum (ESI⁺): m/z = 421 [M + H]⁺ 26[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(4-piperazin-1-yl- phenyl)-methanone  

  The coupling product is obtained from 4-(4-carboxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester usingprocedure A. The tertbutyl ester is cleaved afterwards using theconditions described in Example XXVII. A Mass spectrum (ESI⁺): m/z = 420[M + H]⁺ 27 N-{2-Fluoro-4-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]- phenyl}-acetamide  

A Mass spectrum (ESI⁺): m/z = 411 [M + H]⁺ 281-{4-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocine-3-carbonyl]-phenyl}-ethanone  

A Mass spectrum (ESI⁺): m/z = 378 [M + H]⁺ 295-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]-1-methyl-1,3- dihydro-benzoimidazol-2-one  

A Mass spectrum (ESI⁺): m/z = 406 [M + H]⁺ 303-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocine-3-carbonyl]-benzoicacid methyl ester  

A Mass spectrum (ESI⁺): m/z = 394 [M + H]⁺ 31[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-(1H-indol-6-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 375 [M + H]⁺ 32[3-Ethynyl-4-(pyrrolidine-1-carbonyl)-phenyl]-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 457 [M + H]⁺ 336-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]-1,3-dihydro- indol-2-one  

A Mass spectrum (ESI⁺): m/z = 391 [M + H]⁺ 347-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]-2-methyl-3H- quinazolin-4-one  

A Mass spectrum (ESI⁺): m/z = 418 [M + H]⁺ 35[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-[3-methyl-4-(pyrrolidine-1-carbonyl)-phenyl]-methanone  

A Mass spectrum (ESI⁺): m/z = 447 [M + H]⁺ 364-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocine-3-carbonyl]-N-methyl-benzamide  

A Mass spectrum (ESI⁺): m/z = 393 [M + H]⁺ 374-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]-N,N-dimethyl- benzamide  

A Mass spectrum (ESI⁺): m/z = 407 [M + H]⁺ 383-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]-N,N-dimethyl- benzamide  

A Mass spectrum (ESI⁺): m/z = 407 [M + H]⁺ 393-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocine-3-carbonyl]-N-methyl-benzamide  

A Mass spectrum (ESI⁺): m/z = 393 [M + H]⁺ 40[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-[3-((R)-2-methoxymethyl-pyrrolidine-1-carbonyl)- phenyl]-methanone  

A Mass spectrum (ESI⁺): m/z = 477 [M + H]⁺ 413-[(2R,6S)-10-Hydroxy-6,11,11 -trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocine-3-carbonyl]-benzamide 

A Mass spectrum (ESI⁺): m/z = 379 [M + H]⁺ 423-Chloro-5-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]- benzoic acid methyl ester  

A Mass spectrum (ESI⁺): m/z = 428/430 (Cl) [M + H]⁺ 433-Fluoro-5-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]- benzoic acid methyl ester  

A Mass spectrum (ESI⁺): m/z = 412 [M + H]⁺ 446-[(2R,6S)-10-Hydroxy-6,11,11 -trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]-3,4-dihydro- 1H-quinoxalin-2-one  

A Mass spectrum (ESI⁺): m/z = 406 [M + H]⁺ 45Benzothiazol-5-yl-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]- methanone  

A Mass spectrum (ESI⁺): m/z = 393 [M + H]⁺ 46Benzothiazol-6-yl-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]- methanone  

A Mass spectrum (ESI⁺): m/z = 393 [M + H]⁺ 478-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione  

A Mass spectrum (ESI⁺): m/z = 434 [M + H]⁺ 48[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-(4-methylamino-phenyl)-methanone  

A Mass spectrum (ESI⁺): m/z = 365 [M + H]⁺ 49[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-(1H-indol-5-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 375 [M + H]⁺ 504-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocine-3-carbonyl]-benzoicacid methyl ester  

A Mass spectrum (ESI⁺): m/z = 394 [M + H]⁺ 51(3H-Benzoimidazol-5-yl)-(8-hydroxy-6- methyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 348 [M + H]⁺ 52(3H-Benzoimidazol-5-yl)-[(2R,6R,11S)-8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]- methanone  

A Mass spectrum (ESI⁺): m/z = 362 [M + H]⁺ 53(3H-Benzoimidazol-5-yl)-[(2S,6S,11R)-8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]- methanone  

A Mass spectrum (ESI⁺): m/z = 362 [M + H]⁺ 54(3H-Benzoimidazol-5-yl)-(8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 362 [M + H]⁺ 55(3H-Benzoimidazol-5-yl)-(8-hydroxy-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 334 [M + H]⁺ 56(3H-Benzoimidazol-5-yl)-(6,8-dihydroxy-11,11-dimethyl-1,2,5,6-tetrahydro-4H-4,6-methano-benzo[d]azocin-3-vl)-methanone  

A Mass spectrum (ESI⁺): m/z = 378 [M + H]⁺ 57(3H-Benzoimidazol-5-yl)-(6-hydroxy-11,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 362 [M + H]⁺ 58(3H-Benzoimidazol-5-yl)-(8-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 376 [M + H]⁺ 59(3H-Benzoimidazol-5-yl)-(9-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 376 [M + H]⁺ 60(3H-Benzoimidazol-5-yl)-(1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)- methanone  

A Mass spectrum (ESI⁺): m/z = 318 [M + H]⁺ 61(3H-Benzoimidazol-5-yl)-[(2S,6R)-8-methoxy-6,9,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

  The compound is obtained after resolution of the racemic mixture usingHPLC on chiral phase or using the enantiomerically pure startingmaterial that in turn is obtained by resolution of the racemic mixtureusing HPLC on chiral phase. A Mass spectrum (ESI⁺): m/z = 404 [M + H]⁺62 (3H-Benzoimidazol-5-yl)-[(2R,6S)-8-methoxy-6,9,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

  The compound is obtained after resolution of the racemic mixture usingHPLC on chiral phase or using the enantiomerically pure startingmaterial that in turn is obtained by resolution of the racemic mixtureusing HPLC on chiral phase. A Mass spectrum (ESI⁺): m/z = 404 [M + H]⁺63 (3H-Benzoimidazol-5-yl)-[(2R,6S)-9-methoxy-6,8,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

  The compound is obtained after resolution of the racemic mixture usingHPLC on chiral phase or using the enantiomerically pure startingmaterial that in turn is obtained by resolution of the racemic mixtureusing HPLC on chiral phase. A Mass spectrum (ESI⁺): m/z = 404 [M + H]⁺64 (3H-Benzoimidazol-5-yl)-[(2S,6R)-9-methoxy-6,8,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

  The compound is obtained after resolution of the racemic mixture usingHPLC on chiral phase or using the enantiomerically pure startingmaterial that in turn is obtained by resolution of the racemic mixtureusing HPLC on chiral phase. A Mass spectrum (ESI⁺): m/z = 404 [M + H]⁺65 (3H-Benzoimidazol-5-yl)-[(2R,6S)-8-hydroxy-6,9,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

  The compound is obtained after resolution of the racemic mixture usingHPLC on chiral phase or using the enantiomerically pure startingmaterial that in turn is obtained by resolution of the racemic mixtureusing HPLC on chiral phase. A Mass spectrum (ESI⁺): m/z = 390 [M + H]⁺66 (3H-Benzoimidazol-5-yl)-[(2S,6R)-8-hydroxy-6,9,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

  The compound is obtained after resolution of the racemic mixture usingHPLC on chiral phase or using the enantiomerically pure startingmaterial that in turn is obtained by resolution of the racemic mixtureusing HPLC on chiral phase. A Mass spectrum (ESI⁺): m/z = 390 [M + H]⁺67 (3H-Benzoimidazol-5-yl)-[(2R,6S)-9-hydroxy-6,8,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- a 3-yl]-methanone  

The compound is obtained after resolution of the racemic mixture usingHPLC on chiral phase or using the enantiomerically pure startingmaterial that in turn is obtained by resolution of the racemic mixtureusing HPLC on chiral phase. A Mass spectrum (ESI⁺): m/z = 390 [M + H]⁺68 (3H-Benzoimidazol-5-yl)-[(2S,6R)-9-hydroxy-6,8,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

  The compound is obtained after resolution of the racemic mixture usingHPLC on chiral phase or using the enantiomerically pure startingmaterial that in turn is obtained by resolution of the racemic mixtureusing HPLC on chiral phase. A Mass spectrum (ESI⁺): m/z = 390 [M + H]⁺69 (3H-Benzoimidazol-5-yl)-(6,8,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 374 [M + H]⁺ 70(3H-Benzoimidazol-5-yl)-(8-fluoro-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 378 [M + H]⁺ 71(3H-Benzoimidazol-5-yl)-(9-hydroxy-8- methoxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 406 [M + H]⁺ 72(3H-Benzoimidazol-5-yl)-(8,9-dimethoxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 420 [M + H]⁺ 73(3H-Benzoimidazol-5-yl)-(8-hydroxy-9- methoxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 406 [M + H]⁺ 74(3H-Benzoimidazol-5-yl)-[(2R,6S)-9- methoxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 390 [M + H]⁺ 75(3H-Benzoimidazol-5-yl)-(8-chloro-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 394/396 (Cl) [M + H]⁺ 76(3H-Benzoimidazol-5-yl)-[(2R,6S)-10- methoxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 390 [M + H]⁺ 77(3H-Benzoimidazol-5-yl)-(6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl)-methanone

  compound is a racemic mixture of the pure diastereomer shown A Massspectrum (ESI⁺): m/z = 346 [M + H]⁺ 78(3H-Benzoimidazol-5-yl)-(7-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 376 [M + H]⁺ 79(3H-Benzoimidazol-5-yl)-[(2S,6R)-8- hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 376 [M + H]⁺ 80(3H-Benzoimidazol-5-yl)-[(2R,6S)-8- hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 376 [M + H]⁺ 81[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-(3-methyl-3H-benzoimidazol-5-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 390 [M + H]⁺ 82(3H-Benzoimidazol-5-yl)-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

  The compound is obtained after resolution of the racemic mixture usingHPLC on chiral phase or using the enantiomerically pure startingmaterial that in turn is obtained by resolution of the racemic mixtureusing HPLC on chiral phase. A Mass spectrum (ESI⁺): m/z = 360 [M + H]⁺83 (3H-Benzoimidazol-5-yl)-[(2S,6R,11R)-1,8-dihydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]- methanone  

M Mass spectrum (ESI⁺): m/z = 378 [M + H]⁺ 84(2R,6R,11S)-3-(3H-Benzoimidazole-5- carbonyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8- carbonitrile  

A Mass spectrum (ESI⁺): m/z = 371 [M + H]⁺ 85(3H-Benzoimidazol-5-yl)-(6,11-diethyl-8-hydroxy-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone  

  compound is a racemic mixture of the diastereomer shown A Massspectrum (ESI⁺): m/z = 390 [M + H]⁺ 86(3H-Benzoimidazol-5-yl)-(6,11-diethyl-8-hydroxy-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone  

  compound is a racemic mixture of the diastereomer shown A Massspectrum (ESI⁺): m/z = 390 [M + H]⁺ 87(3H-Benzoimidazol-5-yl)-(6-ethyl-8-hydroxy-11-methyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone  

  compound is a racemic mixture of the diastereomer shown A Massspectrum (ESI⁺): m/z = 376 [M + H]⁺ 88(3H-Benzoimidazol-5-yl)-(8-hydroxy-6-propyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl)-methanone 

A Mass spectrum (ESI⁺): m/z = 376 [M + H]⁺ 89(3H-Benzoimidazol-5-yl)-(6-ethyl-8-hydroxy-11,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 390 [M + H]⁺ 90(3H-Benzoimidazol-5-yl)-(6-ethyl-8-hydroxy-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 362 [M + H]⁺ 91(2R,6R,11S)-3-(3H-Benzoimidazole-5- carbonyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8- carboxylic acid ethyl ester  

A Mass spectrum (ESI⁺): m/z = 418 [M + H]⁺ 92Benzothiazol-6-yl-(8-hydroxy-6-methyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 365 [M + H]⁺ 93(2R,6S)-3-(3H-Benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-10-carbonitrile  

A Mass spectrum (ESI⁺): m/z = 385 [M + H]⁺ 943-(Benzothiazole-6-carbonyl)-8-hydroxy-2,3,4,5-tetrahydro-1H-2,6-methano- benzo[d]azocine-6-carboxylic acidmethyl ester  

  The compound may also be obtained from8-acetoxy-2,3,4,5-tetrahydro-1H-2,6-methano-benzo[d]azocine-6-carboxylic acid methyl ester and treating theamide coupling product with K₂CO₃ in methanol to remove the acetyl groupfrom the phenolic oxygen. A Mass spectrum (ESI⁺): m/z = 409 [M + H]⁺ 95(2R,6S)-3-(1H-Benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-10-carboxylic acid ethyl ester  

A Mass spectrum (ESI⁺): m/z = 432 [M + H]⁺ 963-(1H-Benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-carbonitrile  

A Mass spectrum (ESI⁺): m/z = 385 [M + H]⁺ 973-(1H-Benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-carboxylic acid ethyl ester  

A Mass spectrum (ESI⁺): m/z = 432 [M + H]⁺ 98(3H-Benzoimidazol-5-yl)-(1-methyl-11-aza-tricyclo[8.3.1.0*2,7*]tetradeca-2,4,6-trien-11- yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 346 [M + H]⁺ 99(3H-Benzoimidazol-5-yl)-(4-methoxy-9-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-9-yl)- methanone  

A Mass spectrum (ESI⁺): m/z = 334 [M + H]⁺ 100(3H-Benzoimidazol-5-yl)-(4-hydroxy-9-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-9-yl)- methanone  

A Mass spectrum (ESI⁺): m/z = 320 [M + H]⁺ 101[(2R,6S)-4-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocine-3-carbonyl]-benzoicacid  

  The compound is synthesized using terephthalic acid mono-tert-butylester as the coupling partner in analogy to the procedure A.Subsequently, the tert-butyl ester function is cleaved usingtrifluoroacetic acid in dichloromethane. A Mass spectrum (ESI⁺): m/z =380 [M + H]⁺ 102 (3H-Benzoimidazol-5-yl)-[(2R,6S)-6,11,11-trimethyl-9-phenyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]- methanone  

A Mass spectrum (ESI⁺): m/z = 436 [M + H]⁺ 103(3H-Benzoimidazol-5-yl)-(6-methoxy-11,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 376 [M + H]⁺ 104[(2R,6S)-10-Methoxy-6,11,11-trimethyl-l,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(2-methyl-furan-3-yl)- methanone  

A Mass spectrum (ESI⁺): m/z = 354 [M + H]⁺ 105(8-Hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl)-phenyl-methanone  

A Mass spectrum (ESI⁺): m/z = 322 [M + H]⁺ 106(8-Hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl)-o-tolyl-methanone  

A Mass spectrum (ESI⁺): m/z = 336 [M + H]⁺ 107[(2R,6R,11R)-8-Methoxy-6,11-dimethyl- 1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-pyridin-3-yl-methanone  

A Mass spectrum (ESI⁺): m/z = 337 [M + H]⁺ 108[(2R,6R,11R)-8-Methoxy-6,11-dimethyl- 1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(2-nitro-phenyl)- methanone  

A Mass spectrum (ESI⁺): m/z = 381 [M + H]⁺ 109[(2R,6R,11R)-8-Methoxy-6,11-dimethyl- 1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-o-tolyl-methanone  

A Mass spectrum (ESI⁺): m/z = 350 [M + H]⁺ 110Furan-2-yl-[(2R,6R,11R)-8-methoxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 326 [M + H]⁺ 111[(2R,6R,11R)-8-Methoxy-6,11-dimethyl- 1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(3-methyl-furan-2-yl)- methanone  

A Mass spectrum (ESI⁺): m/z = 340 [M + H]⁺ 112[(2R,6R,11R)-8-Hydroxy-6,11-dimethyl- 1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(3-methyl-furan-2-yl)- methanone  

A Mass spectrum (ESI⁺): m/z = 326 [M + H]⁺ 113Furan-2-yl-[(2R,6R,11R)-8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 312 [M + H]⁺ 114[(2R,6R,11R)-8-Hydroxy-6,11-dimethyl- 1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]pyridin-3-yl-methanone  

A Mass spectrum (ESI⁺): m/z = 323 [M + H]⁺ 115[(2R,6R,11R)-8-Hydroxy-6,11-dimethyl- 1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(2-nitro-phenyl)- methanone  

A Mass spectrum (ESI⁺): m/z = 367 [M + H]⁺ 116[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-(1H-indol-2-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 375 [M + H]⁺ 117(4-Aminomethyl-phenyl)-[(2R,6S)-10- hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

  The acid coupling partner is 4-(tert-butoxycarbonylamino-methyl)-benzoic acid that is liberated from thetert-butoxycarbonyl residue after the amide formation by treatment withtrifluoroacetic acid in dichloromethane A Mass spectrum (ESI⁺): m/z =365 [M + H]⁺ 118 [(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-(1H-indol-3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 375 [M + H]⁺ 119(4-Diethylaminomethyl-phenyl)-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

  The compound is isolated as the trifluoroacetic acid salt A Massspectrum (ESI⁺): m/z = 421 [M + H]⁺ 120[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone  

  The compound is isolated as the trifluoroacetic acid salt A Massspectrum (ESI⁺): m/z = 419 [M + H]⁺ 121(3,5-Dimethyl-isoxazo-4-yl-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 355 [M + H]⁺ 1221-{4-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]-2-methoxy- benzyl}-pyrrolidin-2-one  

A Mass spectrum (ESI⁺): m/z = 463 [M + H]⁺ 123[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(4-imidazol-1-ylmethyl- phenyl)-methanone  

  The compound is isolated as the trifluoroacetic acid salt. A Massspectrum (ESI⁺): m/z = 416 [M + H]⁺ 124(1,5-Dimethyl-1H-pyrazol-3-yl)-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 354 [M + H]⁺ 125N-{4-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocine-3-carbonyl]-benzyl}-benzamide  

A Mass spectrum (ESI⁺): m/z = 469 [M + H]⁺ 126[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-pyridin-4-yl-methanone  

A Mass spectrum (ESI⁺): m/z = 337 [M + H]⁺ 127[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-pyridin-3-yl-methanone  

A Mass spectrum (ESI⁺): m/z = 337 [M + H]⁺ 128[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-pyridin-2-yl-methanone  

A Mass spectrum (ESI⁺): m/z = 337 [M + H]⁺ 129[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-pyrimidin-4-yl-methanone  

A Mass spectrum (ESI⁺): m/z = 338 [M + H]⁺ 130 1-{4-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocine-3-carbonyl]-benzyl}-pyrrolidin-2-one  

A Mass spectrum (ESI⁺): m/z = 432 [M + H]⁺ 131[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(4-[1,2,4]triazol-1- ylmethyl-phenyl)-methanone  

A Mass spectrum (ESI⁺): m/z = 417 [M + H]⁺ 132N-{4-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocine-3-carbonyl]-benzyl}-acetamide  

A Mass spectrum (ESI⁺): m/z = 407 [M + H]⁺ 133[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-[4-(pyrrolidine-1- carbonyl)-phenyl]-methanone  

A Mass spectrum (ESI⁺): m/z = 433 [M + H]⁺ 134[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-[4-(morpholine-4- carbonyl)-phenyl]-methanone  

A Mass spectrum (ESI⁺): m/z = 449 [M + H]⁺ 1354-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocine-3-carbonyl]-N-phenyl-benzamide  

A Mass spectrum (ESI⁺): m/z = 455 [M + H]⁺ 136[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-methanone  

  The compound is isolated as the trifluoroacetic acid salt. A Massspectrum (ESI⁺): m/z = 462 [M + H]⁺ 137N-Benzyl-4-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]- benzamide  

A Mass spectrum (ESI⁺): m/z = 469 [M + H]⁺ 138N-Ethyl-4-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]- benzamide  

A Mass spectrum (ESI⁺): m/z = 407 [M + H]⁺ 139(3H-Benzoimidazol-5-yl)-[(2R,6S)-6,10,11,11-tetramethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]- methanone  

A Mass spectrum (ESI⁺): m/z = 374 [M + H]⁺ 140(3H-Benzoimidazol-5-yl)-[(2R,6S)-10-fluoro-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 378 [M + H]⁺ 141(9-Amino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-(3H-benzoimidazol-5-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 375 [M + H]⁺ 142N-Ethyl-4-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]- benzamide  

  The compound is isolated as its trifluoroacetic acid salt A Massspectrum (ESI⁺): m/z = 449 [M + H]⁺ 143(8,9-Methylenedioxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-(3H-benzoimidazol-5- yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 404 [M + H]⁺ 144(3-Chloro-pyridin-4-yl)-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 371/373 (Cl) [M + H]⁺ 145(3H-Benzoimidazol-5-yl)-(9-fluoro-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 378 [M + H]⁺ 146(3H-Benzoimidazol-5-yl)-(10-methoxy-11,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 376 [M + H]⁺ 147(3H-Benzoimidazol-5-yl)-[(2S,6R)-9- methoxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 390 [M + H]⁺ 148(3H-Benzoimidazol-5-yl)-(6-phenyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl)-methanone  

  The starting material, 6-phenyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine, is obtained as described in J.Org. Chem. 1966, 31, 1905-11. A Mass spectrum (ESI⁺): m/z = 394 [M + H]⁺149 (3H-Benzoimidazol-5-yl)-(8-hydroxy-6-phenyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl)-methanone 

  The starting material, 6-phenyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8- ol, is obtained as described inJ. Med. Chem. 1969, 12, 845-847. A Mass spectrum (ESI⁺): m/z = 410 [M +H]⁺ 150 (3H-Benzoimidazol-5-yl)-(8-hydroxy-11,11-dimethyl-6-phenyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)- methanone  

A Mass spectrum (ESI⁺): m/z = 438 [M + H]⁺ 151(2R,6R,11S)-3-(3H-Benzoimidazole-5- carbonyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8- carboxylic acid  

B Mass spectrum (ESI⁺): m/z = 390 [M + H]⁺ 152(2R,6S)-3-(3H-Benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-10-carboxylic acid  

B Mass spectrum (ESI⁺): m/z = 404 [M + H]⁺ 1533-(Benzothiazole-6-carbonyl)-8-hydroxy-2,3,4,5-tetrahydro-1H-2,6-methano- benzo[d]azocine-6-carboxylic acid  

B Mass spectrum (ESI⁺): m/z = 395 [M + H]⁺ 1543-(3H-Benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-carboxylic acid  

B Mass spectrum (ESI⁺): m/z = 404 [M + H]⁺ 155(2R,6R,11S)-3-(3H-Benzoimidazole-5- carbonyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8- carboxylic acid dimethylamide  

C Mass spectrum (ESI⁺): m/z = 417 [M + H]⁺ 156(2R,6R,11S)-3-(3H-Benzoimidazole-5- carbonyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8 carboxylic acid methylamide  

  Aminomethane is used as coupling partner. C Mass spectrum (ESI⁺): m/z= 403 [M + H]⁺ 157 (2R,6R,11S)-3-(3H-Benzoimidazole-5-carbonyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8- carboxylic acid amide  

  Ammonia is used as coupling partner. C Mass spectrum (ESI⁺): m/z = 389[M + H]⁺ 158 (2R,6S)-3-(3H-Benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-10-carboxylic acid dimethylamide  

C Mass spectrum (ESI⁺): m/z = 431 [M + H]⁺ 159(2R,6S)-3-(3H-Benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-10-carboxylic acid methylamide  

  Aminomethane is used as coupling partner. C Mass spectrum (ESI⁺): m/z= 417 [M + H]⁺ 160 (2R,6S)-3-(3H-Benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-10-carboxylic acid amide  

  Ammonia is used as coupling partner. C Mass spectrum (ESI⁺): m/z = 403[M + H]⁺ 161 3-(3H-Benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-carboxylic acid dimethylamide  

C Mass spectrum (ESI⁺): m/z = 431 [M + H]⁺ 1623-(3H-Benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-carboxylic acid methylamide  

  Aminomethane is used as coupling partner. C Mass spectrum (ESI⁺): m/z= 417 [M + H]⁺ 163 3-(3H-Benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-carboxylic acid amide  

  Ammonia is used as coupling partner. C Mass spectrum (ESI⁺): m/z = 403[M + H]⁺ 164 3-(Benzothiazole-6-carbonyl)-8-hydroxy-2,3,4,5-tetrahydro-1H-2,6-methano- benzo[d]azocine-6-carboxylic aciddimethylamide  

C Mass spectrum (ESI⁺): m/z = 422 [M + H]⁺ 1653-(Benzothiazole-6-carbonyl)-8-hydroxy-2,3,4,5-tetrahydro-1H-2,6-methano- benzo[d]azocine-6-carboxylic acidmethylamide  

  Aminomethane is used as coupling partner. C Mass spectrum (ESI⁺): m/z= 408 [M + H]⁺ 166 3-(Benzothiazole-6-carbonyl)-8-hydroxy-2,3,4,5-tetrahydro-1H-2,6-methano- benzo[d]azocine-6-carboxylic acidamide  

  Ammonia is used as coupling partner. C Mass spectrum (ESI⁺): m/z = 394[M + H]⁺ 167 4-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]-N-methyl-N- propyl-benzamide  

  The compound is synthesized from 4-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocine-3-carbonyl]-benzoicacid and methylpropylamine as described in the procedure C. C Massspectrum (ESI⁺): m/z = 435 [M + H]⁺ 168N,N-Diethyl-4-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]- benzamide  

  The compound is synthesized from 4-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocine-3-carbonyl]-benzoicacid and dimethylamine as described in the procedure C. C Mass spectrum(ESI⁺): m/z = 435 [M + H]⁺ 169 [(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-[4-(piperidine-1- carbonyl)-phenyl]-methanone  

  The compound is synthesized from 4-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocine-3-carbonyl]-benzoicacid and piperidine as described in the procedure C. C Mass spectrum(ESI⁺): m/z = 447 [M + H]⁺ 170 N-Benzyl-4-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]-N- methyl-benzamide  

  The compound is synthesized from 4-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocine-3-carbonyl]-benzoicacid and benzylmethylamine as described in the procedure C. C Massspectrum (ESI⁺): m/z = 483 [M + H]⁺ 1714-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocine-3-carbonyl]-N-propyl-benzamide  

  The compound is synthesized from 4-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocine-3-carbonyl]-benzoicacid and n-propylamine as described in the procedure C. C Mass spectrum(ESI⁺): m/z = 421 [M + H]⁺ 172 [(2R,6R,11S)-8-Aminomethyl-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(3H-benzoimidazol-5- yl)-methanone  

D Mass spectrum (ESI⁺): m/z = 375 [M + H]⁺ 173(9-Aminomethyl-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-(3H-benzoimidazol-5-yl)-methanone  

D Mass spectrum (ESI⁺): m/z = 389 [M + H]⁺ 174Benzothiazol-6-yl-(6-methyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl)-methanone  

E Mass spectrum (ESI⁺): m/z = 349 [M + H]⁺ 1753-(1H-Benzoimidazole-5-carbonyl)-N- hydroxy-6,11,11-trimethyl-1,2,3,4,5,6- hexahydro-2,6-methano-benzo[d]azocine-9-carboxamidine  

F Mass spectrum (ESI⁺): m/z = 418 [M + H]⁺ 176(1H-Benzoimidazol-5-yl)-[6,11,11-trimethyl-9-(5-methyl-[1,2,4]oxadiazol-3-yl)-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

G Mass spectrum (ESI⁺): m/z = 442 [M + H]⁺ 1773-(Benzothiazole-6-carbonyl)-8-hydroxy-2,3,4,5-tetrahydro-1H-2,6-methano- benzo[d]azocine-6-carbonitrile  

H Mass spectrum (ESI⁺): m/z = 476 [M + H]⁺ 178N-[3-(3H-Benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-9-ylmethyl]- acetamide  

I Mass spectrum (ESI⁺): m/z = 431 [M + H]⁺ 179N-[3-(3H-Benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-9-yl]-acetamide  

I Mass spectrum (ESI⁺): m/z = 417 [M + H]⁺ 180[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(2-methyl-furan-3-yl)- methanone  

J Mass spectrum (ESI⁺): m/z = 340 [M + H]⁺ 181N-[3-(3H-Benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-9-yl]- methanesulfonamide  

K Mass spectrum (ESI⁺): m/z = 453 [M + H]⁺ 1824-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocine-3-carbonyl]-benzoicacid  

  The compound is synthesized from coupling with4-tert-butoxycarbonylbenzoic acid according to procedure A andsubsequent cleavage of the tertbutyl ester with trifluoroacetic acid indichloromethane A Mass spectrum (ESI⁺): m/z = 380 [M + H]⁺ 183(3H-Benzoimidazol-5-yl)-(10-hydroxy-11,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone  

L Mass spectrum (ESI⁺): m/z = 362 [M + H]⁺ 184[4-(2,6-Dimethyl-morpholin-4-ylmethyl)-phenyl]-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

  The compound is isolated as its trifluoroacetic acid salt A Massspectrum (ESI⁺): m/z = 463 [M + H]⁺ 185[4-(4-Hydroxy-4-methyl-piperidin-1-ylmethyl)-phenyl]-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6methano-benzo[d]azocin-3-yl]-methanone  

  The compound is isolated as its trifluoroacetic acid salt A Massspectrum (ESI⁺): m/z = 463 [M + H]⁺ 186[4-(endo-3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-ylmethyl)-phenyl]-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

  The compound is isolated as its trifluoroacetic acid salt A Massspectrum (ESI⁺): m/z = 475 [M + H]⁺ 187[4-(3-Hydroxy-azetidin-1-ylmethyl)-phenyl]-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-methanone  

  The compound is isolated as its trifluoroacetic acid salt A Massspectrum (ESI⁺): m/z = 421 [M + H]⁺ 188[4-(3-Hydroxy-pyrrolidin-1-ylmethyl)-phenyl]-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

  The compound is isolated as its trifluoroacetic acid salt A Massspectrum (ESI⁺): m/z = 435 [M + H]⁺ 189[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-[4-(4-methoxy-piperidin-1-ylmethyl)-phenyl]-methanone  

  The compound is isolated as its trifluoroacetic acid salt A Massspectrum (ESI⁺): m/z = 463 [M + H]⁺ 190[4-(4-Hydroxy-piperidin-1-ylmethyl)-phenyl]-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-methanone  

  The compound is isolated as its trifluoroacetic acid salt A Massspectrum (ESI⁺): m/z = 449 [M + H]⁺ 191(3H-Benzoimidazol-5-yl)-[(5R,9S)-4,5,6,7,8,9-hexahydro-2,10,12,12-trimethyl- 5,9-methano-1H-imidazo[5,4-j][3]benzazocin-6-yl]-methanone  

  The compound is isolated as its trifluoroacetic acid salt A Massspectrum (ESI⁺): m/z = 400 [M + H]⁺ 192[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(1H-indazol-3-yl)- methanone  

A Mass spectrum (ESI⁺): m/z = 376 [M + H]⁺ 193(5-Fluoro-1H-indol-3-yl)-[(2R,6S)-10- hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 393 [M + H]⁺ 194[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(1-methyl-1H-indazol- 3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 390 [M + H]⁺ 195[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(4-methoxy-1H-indol-3- yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 405 [M + H]⁺ 196(5-Chloro-1H-indol-3-yl)-[(2R,6S)-10- hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 409/411 (Cl) [M + H]⁺ 197[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(2-methyl-1H-indol-3- yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 389 [M + H]⁺ 198Benzofuran-3-yl-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 376 [M + H]⁺ 199[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(1-methyl-1H-indol-3- yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 389 (Cl) [M + H]⁺ 200(3H-Benzoimidazol-5-yl)-(6-ethyl-8-hydroxy-11-methyl-1,2,5,6-tetrahydro-4H-2,6- methano-benzo[d]azocin-3-yl)-methanone  

  compound is a racemic mixture of the diastereomer shown A Massspectrum (ESI⁺): m/z = 390 [M + H]⁺ 201(2R,6S)-3-(3H-Benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-sulfonic acid dimethylamide  

A Mass spectrum (ESI⁺): m/z = 467 [M + H]⁺ 202(2R,6S)-3-(3H-Benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-sulfonic acid methylamide  

A Mass spectrum (ESI⁺): m/z = 453 [M + H]⁺ 203(2R,6S)-3-(3H-Benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-sulfonic acid amide  

A Mass spectrum (ESI⁺): m/z = 439 [M + H]⁺ 2041-[(2R,6S)-3-(3H-Benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8- yl]-ethanone  

A Mass spectrum (ESI⁺): m/z = 402 [M + H]⁺ 2051-[(2R,6S)-3-(3H-Benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-9- a yl]-ethanone  

A Mass spectrum (ESI⁺): m/z = 402 [M + H]⁺ 206(2R,6S)-3-(3H-Benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-carbonitrile  

A Mass spectrum (ESI⁺): m/z = 385 [M + H]⁺ 2074-[(2R,6S)-4-(10-Hydroxy-6,11,11-trimethyl1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocine-3-carbonyl)-benzyl]-morpholin-3-one  

  the coupling partner, 4-(3-oxo-morpholin-4- ylmethyl)-benzoic acid, isobtained from 3- oxo-morpholine and 4-bromomethylbenzoic acid using NaHas base and NMP as solvent followed by hydrolysis with KOH in MeOH AMass spectrum (ESI⁺): m/z = 449 [M + H]⁺ 2084-[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]-N-methyl-N- phenyl-benzamide  

A Mass spectrum (ESI⁺): m/z = 469 [M + H]⁺ 209(3H-Benzoimidazol-5-yl)-[(2R,6S)-9-(1-hydroxy-ethyl)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

M Mass spectrum (ESI⁺): m/z = 404 [M + H]⁺ 210[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-(6-methyl-3H-benzoimidazol-5-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 390 [M + H]⁺ 211(3H-Benzoimidazol-5-yl)-[(2R,6S)-8-(1-hydroxy-ethyl)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

M Mass spectrum (ESI⁺): m/z = 404 [M + H]⁺ 2123-(3H-Benzoimidazole-5-carbonyl)-8-hydroxy-2,3,4,5-tetrahydro-1H-2,6-methano- benzo[d]azocine-6-carboxylicacid methyl ester  

A Mass spectrum (ESI⁺): m/z = 392 [M + H]⁺ 2133-(3H-Benzoimidazole-5-carbonyl)-8-hydroxy-2,3,4,5-tetrahydro-1H-2,6-methano- benzo[d]azocine-6-carboxylicacid  

B Mass spectrum (ESI⁺): m/z = 378 [M + H]⁺ 2143-(3H-Benzoimidazole-5-carbonyl)-8-hydroxy-2,3,4,5-tetrahydro-1H-2,6-methano- benzo[d]azocine-6-carboxylicacid amide  

A Mass spectrum (ESI⁺): m/z = 377 [M + H]⁺ 215(2,5-Dimethyl-2H-pyrazol-3-yl)-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 354 [M + H]⁺ 216[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(2-phenyl-2H-pyrazol- 3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 402 [M + H]⁺ 217Benzo[b]thiophen-3-yl-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 392 [M + H]⁺ 218[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(3-phenyl-3H-imidazol- 4-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 402 [M + H]⁺ 219[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(4,5,6,7-tetrahydro- 1H-indazol-3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 380 [M + H]⁺ 220[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 366 [M + H]⁺ 221[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(5-phenyl-2H-pyrazol- 3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 402 [M + H]⁺ 222(1-Ethyl-1H-indol-3-yl)-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 403 [M + H]⁺ 223(2R,6R,11S)-3-(3H-Benzoimidazole-5- carbonyl)-8-hydroxy-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano- benzo[d]azocine-9-carbonitrile  

A Mass spectrum (ESI⁺): m/z = 387 [M + H]⁺ 224(3H-Benzoimidazol-5-yl)-[(6R,10R,12S)-5,6,7,8,9,10-hexahydro-10,12-dimethyl- 6,10-methano-1H-imidazo[5,4-i][3]benzazocin-7-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 386 [M + H]⁺ 225[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-(7-methyl-1H-benzoimidazol-5-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 390 [M + H]⁺ 2263-(3H-Benzoimidazole-5-carbonyl)-8-hydroxy-2,3,4,5-tetrahydro-1H-2,6-methano-benzo[d]azocine-6-carbonitrile  

H Mass spectrum (ESI⁺): m/z = 359 [M + H]⁺ 227(2R,6R,11S)-3-(3H-Benzoimidazole-5- carbonyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9- carbonitrile  

A Mass spectrum (ESI⁺): m/z = 387 [M + H]⁺ 228(2R,6R,11S)-(3H-Benzoimidazol-5-yl)-[6,11-dimethyl-8-(1H-tetrazol-5-yl)-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

N Mass spectrum (ESI⁺): m/z = 414 [M + H]⁺ 229(3H-Benzoimidazol-5-yl)-[(2R,6S)-8-(1-hydroxy-1-methyl-ethyl)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-methanone  

O Mass spectrum (ESI⁺): m/z = 418 [M + H]⁺ 230(2R,6R,11S)-3-(3H-Benzoimidazole-5- carbonyl)-N-hydroxy-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano- benzo[d]azocine-8-carboxamidine  

F Mass spectrum (ESI⁺): m/z = 404 [M + H]⁺ 231(3H-Benzoimidazol-5-yl)-[(2R,6R,11S)-6,11-dimethyl-8-(5-methyl-[1,2,4]oxadiazol-3-yl)-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]- methanone 

G Mass spectrum (ESI⁺): m/z = 428 [M + H]⁺ 232(3H-Benzoimidazol-5-yl)-[(2R,6R,11S)-6,11-dimethyl-8-[1,2,4]oxadiazol-3-yl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-methanone  

P Mass spectrum (ESI⁺): m/z = 414 [M + H]⁺ 233(3H-Benzoimidazol-5-yl)-[(2R,6S)-8-methanesulfonyl-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 438 [M + H]⁺ 234(3H-Benzoimidazol-5-yl)-[(2R,6S)-10-methanesulfonyl-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 438 [M + H]⁺ 235(3H-Benzoimidazol-5-yl)-[(7R,11S)-6,7,8,9,10,11-hexahydro-11,13,13-trimethyl-6,10-methano-pyrazino[2,3-i][3]benzazocin- 8-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 412 [M + H]⁺ 236(2R,6R,11R)-3-(3H-Benzoimidazole-5-carbonyl)-6,11-dimethyl-1,2,3,4,5,6,8,9-octahydro-2,6-methano-benzo[d]azocine-9- carbonitrile  

A Mass spectrum (ESI⁺): m/z = 371 [M + H]⁺ 237(2R,6S)-3-(3H-Benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-9-sulfonic acid dimethylamide  

A Mass spectrum (ESI⁺): m/z = 467 [M + H]⁺ 238(3H-Benzoimidazol-5-yl)-[(6R,10S)- 5,6,7,8,9,10-hexahydro-2,10,12,12-tetramethyl-6,10-methano-1H-imidazo[5,4- i][3]benzazocin-7-yl]-methanone 

A Mass spectrum (ESI⁺): m/z = 414 [M + H]⁺ 239(3H-Benzoimidazol-5-yl)-[(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl- 6,10-methano-1H-imidazo[5,4-i][3]benzazocin-7-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 400 [M + H]⁺ 240(3H-Benzoimidazol-5-yl)-[(6R,10S)- 5,6,7,8,9,10-hexahydro-3,10,12,12-tetramethyl-6,10-methano-imidazo[4,5- i][3]benzazocin-7-yl]-methanone  

  the mixture of Example L was used as starting material; the compoundwas separated from compound Example 241 by HPLC on reversed phase A Massspectrum (ESI⁺): m/z = 414 [M + H]⁺ 241(3H-Benzoimidazol-5-yl)-[(6R,10S)- 5,6,7,8,9,10-hexahydro-1,10,12,12-tetramethyl-6,10-methano-imidazo[5,4- i][3]benzazocin-7-yl]-methanone  

  the mixture of Example L was used as starting material; the compoundwas separated from compound Example 240 by HPLC on reversed phase A Massspectrum (ESI⁺): m/z = 414 [M + H]⁺ 242(3H-Benzoimidazol-5-yl)-[(6R,10S)- 5,6,7,8,9,10-hexahydro-1,2,10,12,12-pentamethyl-6,10-methano-imidazo[5,4- i][3]benzazocin-7-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 428 [M + H]⁺ 243(3H-Benzoimidazol-5-yl)-[(6R,10S)- 5,6,7,8,9,10-hexahydro-2,3,10,12,12-pentamethyl-6,10-methano-imidazo[4,5- i][3]benzazocin-7-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 428 [M + H]⁺ 244(3H-Benzoimidazol-5-yl)-[(7R,11S)- 6,7,8,9,10,11-hexahydro-2,3,11,13,13-pentamethyl-7,11-methano-pyrazino[2,3- i][3]benzazocin-8-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 440 [M + H]⁺ 245(3H-Benzoimidazol-5-yl)-(2,3,4,5,6,7-hexahydro-2,6-methano-azocino[5,4-b]indol- 3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 357 [M + H]⁺ 246(3H-Benzoimidazol-5-yl)-[(2S,6S,11S)-8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)- methanone  

A Mass spectrum (ESI⁺): m/z = 362 [M + H]⁺ 247(3H-Benzoimidazol-5-yl)-[(2R,6R,11R)-8-hydroxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)- methanone  

A Mass spectrum (ESI⁺): m/z = 362 [M + H]⁺ 248[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-(5-methyl-1H-indol-3- yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 389 [M + H]⁺ 249(3H-Benzoimidazol-5-yl)-[(2R,6R,11S)-6,11-dimethyl-8-phenyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)- methanone  

A Mass spectrum (ESI⁺): m/z = 422 [M + H]⁺ 250(3H-Benzoimidazol-5-yl)-[(2R,6R,11S)-6,11-dimethyl-8-pyridin-3-yl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 423 [M + H]⁺ 251(3H-Benzoimidazol-5-yl)-[(2R,6R,11S)-6,11-dimethyl-8-pyridin-4-yl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 423 [M + H]⁺ 252(3H-Benzoimidazol-5-yl)-[(2R,6R,11S)-6,11-dimethyl-8-pyrimidin-5-yl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 424 [M + H]⁺ 253(3H-Benzoimidazol-5-yl)-(4,6-dimethyl 1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone  

  racemic mixture of diastereomer shown A Mass spectrum (ESI⁺): m/z =346 [M + H]⁺ 254 (3H-Benzoimidazol-5-yl)-[(7R,11S)-6,7,8,9,10,11-hexahydro-3,11,13,13-tetramethyl-7,11-methano-pyrazino[2,3- i][3]benzazocin-8-yl]-methanone  

  the compound is obtained in a mixture with compound Example 255 A Massspectrum (ESI⁺): m/z = 426 [M + H]⁺ 255(3H-Benzoimidazol-5-yl)-[(7R,11S)- 6,7,8,9,10,11-hexahydro-2,11,13,13-tetramethyl-7,11-methano-pyrazino[2,3- i][3]benzazocin-8-yl]-methanone  

  the compound is obtained in a mixture with compound Example 254 A Massspectrum (ESI⁺): m/z = 426 [M + H]⁺ 256(1-Methyl-1H-indol-3-yl)-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 373 [M + H]⁺ 257(3H-Benzoimidazol-5-yl)-[(6R,10S)- 5,6,7,8,9,10-hexahydro-1,10,12,12-tetramethyl-6,10-methano-triazolo[5,4- i][3]benzazocin-7-yl]-methanone  

the compound is obtained in a mixture with compound Example 258 whichwas separated by HPLC on chiral phase A Mass spectrum (ESI⁺): m/z = 415[M + H]⁺ 258 (3H-Benzoimidazol-5-yl)-[(6R,10S)-5,6,7,8,9,10-hexahydro-3,10,12,12-tetramethyl-6,10-methano-triazolo[4,5- i][3]benzazocin-7-yl]-methanone  

the compound is obtained in a mixture with compound Example 257 whichwas separated by HPLC on chiral phase A Mass spectrum (ESI⁺): m/z = 415[M + H]⁺ 259 (1H-Indol-3-yl)-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 359 [M + H]⁺ 260[(2R,6S)-10-Hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-[3-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-phenyl]-methanone  

A Mass spectrum (ESI⁺): m/z = 448 [M + H]⁺ 261(3H-Benzoimidazol-5-yl)-[(2R,6R,11S)-8-methoxy-6,11-dimethyl-7-nitro-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 421 [M + H]⁺ 262(3H-Benzoimidazol-5-yl)-[(2R,6R,11S)-6,11-dimethyl-8-(2-methyl-pyrimidin-4-yl)-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 438 [M + H]⁺ 263(3H-Benzoimidazol-5-yl)-[(2R,6R,11S)-6,11-dimethyl-8-(6-methyl-pyridazin-3-yl)-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 438 [M + H]⁺ 264(3H-Benzoimidazol-5-yl)-[(2R,6R,11S)-6,11-dimethyl-8-pyrimidin-4-yl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 424 [M + H]⁺ 265(3H-Benzoimidazol-5-yl)-[(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl- 6,10-methano-1H-triazolo[5,4-i][3]benzazocin-7-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 401 [M + H]⁺ 266(3H-Benzoimidazol-5-yl)-[(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-2-pyrazin-2-yl-6,10-methano-imidazo[5,4- i][3]benzazocin-7-yl]-methanone 

A Mass spectrum (ESI⁺): m/z = 478 [M + H]⁺ 267(3H-Benzoimidazol-5-yl)-[(2R,6R,11S)-7-amino-8-methoxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

Q Mass spectrum (ESI⁺): m/z = 391 [M + H]⁺ 268N-[(2R,6R,11S)-3-(3H-Benzoimidazole-5-carbonyl)-8-methoxy-6,11-dimethyl- 1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-7-yl]-methanesulfonamide  

K Mass spectrum (ESI⁺): m/z = 469 [M + H]⁺ 269[(6R,10S)-2-(1-Acetyl-piperidin-4-yl)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-6,10-methano-imidazo[5,4-i][3]benzazocin-7-yl]-(3H-benzoimidazol-5-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 525 [M + H]⁺ 270(3H-Benzoimidazol-5-yl)-[(2R,6R,11S)-8-methoxy-6,11-dimethyl-7-pyrrol-1-yl-1,2,5,6- tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone  

R Mass spectrum (ESI⁺): m/z = 441 [M + H]⁺ 271(3H-Benzoimidazol-5-yl)-[(6R,10S)-2- cyclopropyl-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-6,10-methano-imidazo[5,4-i][3]benzazocin-7-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 440 [M + H]⁺ 272(3H-Benzoimidazol-5-yl)-[(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-2-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6,10-methano-imidazo[5,4-i][3]benzazocin- 7-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 507 [M + H]⁺ 273(3H-Benzoimidazol-5-yl)-[(6R,10S)-2-tert-butyl-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-6,10-methano-imidazo[5,4- i][3]benzazocin-7-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 456 [M + H]⁺ 274(3H-Benzoimidazol-5-yl)-[(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-2-pyridin-3-yl-6,10-methano-imidazo[5,4- i][3]benzazocin-7-yl]-methanone 

A Mass spectrum (ESI⁺): m/z = 477 [M + H]⁺ 275(3H-Benzoimidazol-5-yl)-[(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-2-[(S)-tetrahydrofuran-2-yl]-6,10-methano-imidazo[5,4-i][3]benzazocin-7-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 470 [M + H]⁺ 276(3H-Benzoimidazol-5-yl)-[(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-2-pyridazin-4-yl-6,10-methano-imidazo[5,4-i][3]benzazocin-7-yl]-methanone  

  the compound was isolated as its F₃CO₂H salt A Mass spectrum (ESI⁺):m/z = 478 [M + H]⁺ 277 (3H-Benzoimidazol-5-yl)-[(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-2-(5-methyl-pyrazin-2-yl)-6,10-methano-imidazo[5,4-i][3]benzazocin-7-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 492 [M + H]⁺ 278Quinoxalin-6-yl-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 372 [M + H]⁺ 279(3H-Benzoimidazol-5-yl)-[(2R,6R,11S)-6,11-dimethyl-8-(1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]- methanone  

A Mass spectrum (ESI⁺): m/z = 453 [M + H]⁺ 280(4-Nitro-phenyl)-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 365 [M + H]⁺ 281(4-Amino-2,3,5,6-tetrafluoro-phenyl)-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]- methanone  

A Mass spectrum (ESI⁺): m/z = 407 [M + H]⁺ 282Naphthalen-2-yl-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 370 [M + H]⁺ 283(4-Amino-3,5-dichloro-phenyl)-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 403/405/407 (2Cl) [M + H]⁺ 284Naphthalen-1-yl-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 370 [M + H]⁺ 285(1H-Indazol-6-yl)-[(2R,6S)-6,11,11- trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 360 [M + H]⁺ 286(4-Amino-phenyl)-[(2R,6S)-6,11,11- trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 335 [M + H]⁺ 287(3H-Benzoimidazol-5-yl)-[(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-2-[(R)-tetrahydrofuran-2-yl]-6,10-methano-imidazo[5,4-i][3]benzazocin-7-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 470 [M + H]⁺ 2886-[(2R,6S)-6,11,11-Trimethyl-1,2,5,6- tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl)-indan-1-one  

A Mass spectrum (ESI⁺): m/z = 374 [M + H]⁺ 2895-[(2R,6R,11S)-3-(3H-Benzoimidazole-5-carbonyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8- yl]-1-methyl-1H-pyridin-2-one  

A Mass spectrum (ESI⁺): m/z = 453 [M + H]⁺ 2906-[(2R,6R,11S)-3-(3H-Benzoimidazole-5-carbonyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8- yl]-2-methyl-2H-pyridazin-3-one 

A Mass spectrum (ESI⁺): m/z = 454 [M + H]⁺ 291(3-Hydroxy-indan-5-yl)-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

M Mass spectrum (ESI⁺): m/z = 376 [M + H]⁺ 292(3-Hydroxy-3-methyl-indan-5-yl)-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]- methanone  

O Mass spectrum (ESI⁺): m/z = 390 [M + H]⁺ 293(1H-Indazol-5-yl)-[(2R,6S)-6,11,11- trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 360 [M + H]⁺ 294(3H-Benzoimidazol-5-yl)-(5,6-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl)-methanone  

  (racemic mixture of diastereomer shown) A Mass spectrum (ESI⁺): m/z =346 [M + H]⁺ 295 (4-Amino-3-chloro-phenyl)-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 369/371 (Cl) [M + H]⁺ 296(4-Amino-3-fluoro-phenyl)-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 353 [M + H]⁺ 297(3,4,5-Trifluoro-phenyl)-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 374 [M + H]⁺ 2985-[(2R,6S)-6,11,11-Trimethyl-1,2,5,6- tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]-1,3-dihydro indol-2-one  

A Mass spectrum (ESI⁺): m/z = 375 [M + H]⁺ 2991-{4-([(2R,6S)-6,11,11-Trimethyl-1,2,5,6- tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]-phenyl}- ethanone  

A Mass spectrum (ESI⁺): m/z = 362 [M + H]⁺ 300(3H-Benzoimidazol-5-yl)-[(7R,11R,12S)-6,7,8,9,10,11-hexahydro-2,11,12-trimethyl-6,10-methano-oxazolo[4,5-h][3]benzazocin- 8-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 401 [M + H]⁺ 301(3H-Benzoimidazol-5-yl)-[(6R,10S)- 5,6,7,8,9,10-hexahydro-2,10,12,12-tetramethyl-6,10-methano-oxazolo[4,5- i][3]benzazocin-7-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 415 [M + H]⁺ 302(3H-Benzoimidazol-5-yl)-[(6R,10S)-2- cyclopropyl-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-6,10-methano-oxazolo[4,5-i][3]benzazocin-7-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 441 [M + H]⁺ 303(6-Hydroxy-pyridin-3-yl)-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 337 [M + H]⁺ 304(6-Amino-pyridin-3-yl)-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 336 [M + H]⁺ 305(3H-Benzoimidazol-5-yl)-[(6R,10R,12S)-5,6,7,8,9,10-hexahydro-2,10,12-trimethyl-6,10-methano-oxazolo[5,4-i][3]benzazocin 7-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 401 [M + H]⁺ 306[4-(1-Hydroxy-1-methyl-ethyl)-phenyl]-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]- methanone  

O Mass spectrum (ESI⁺): m/z = 378 [M + H]⁺ 3071-{3-[(2R,6S)-6,11,11-Trimethyl-1,2,5,6- tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]-phenyl}- ethanone  

A Mass spectrum (ESI⁺): m/z = 362 [M + H]⁺ 3083,3-Dimethyl-5-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]-1,3-dihydro- indol-2-one  

A Mass spectrum (ESI⁺): m/z = 403 [M + H]⁺ 309(1H-Benzoimidazol-5-yl)-(6,11,11-trimethyl-7-pyridin-3-yl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 437 [M + H]⁺ 310[3-(1-Hydroxy-ethyl)-phenyl]-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]- methanone  

M Mass spectrum (ESI⁺): m/z = 364 [M + H]⁺ 311(3H-Benzoimidazol-5-yl)-[(6R,10R,12S)-2-cyclopropyl-5,6,7,8,9,10-hexahydro-10,12-dimethyl-6,10-methano-oxazolo[5,4- i][3]benzazocin-7-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 427 [M + H]⁺ 312(3H-Benzoimidazol-5-yl)-[(6R,10S)-2-tert-butyl-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-6,10-methano-oxazolo[4,5- i][3]benzazocin-7-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 457 [M + H]⁺ 313(3H-Benzoimidazol-5-yl)-[(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-2-(5-methyl-pyrazin-2-yl)-6,10-methano-oxazolo[4,5-i][3]benzazocin-7-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 493 [M + H]⁺ 314[3-(1-Hydroxy-ethyl)-phenyl]-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]- methanone  

M Mass spectrum (ESI⁺): m/z = 364 [M + H]⁺ 315(3H-Benzoimidazol-5-yl)-[(2R,6R,11S)-6,11-dimethyl-8-(2-methyl-pyrimidin-5-yl)-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 438 [M + H]⁺ 3163-(1H-Benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-7-carbonitrile  

A Mass spectrum (ESI⁺): m/z = 437 [M + H]⁺ 317[3-(1-Hydroxy-1-methyl-ethyl)-phenyl]-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin- 3-yl]-methanone  

O Mass spectrum (ESI⁺): m/z = 378 [M + H]⁺ 318(4-Hydroxy-phenyl)-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 336 [M + H]⁺ 319(3-Hydroxy-phenyl)-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 336 [M + H]⁺ 320(3,5-Dichloro-4-hydroxy-phenyl)-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 404/406/408 (2Cl) [M + H]⁺ 321(3H-Benzoimidazol-5-yl)-(5-methoxy- 3,3a,8,8a-tetrahydro-2H-1-aza-cyclopenta[a]inden-1-yl)-methanone  

  The starting material, 5-methoxy- 1,2,3,3a,8,8a-hexahydro-1-aza-cyclopenta[a]indene, is obtained as described in WO 9200961 A Massspectrum (ESI⁺): m/z = 334 [M + H]⁺ 322(3H-Benzoimidazol-5-yl)-(5-hydroxy- 3,3a,8,8a-tetrahydro-2H-1-aza-cyclopenta[a]inden-1-yl)-methanone  

J or as described in Example XIII Mass spectrum (ESI⁺): m/z = 320 [M +H]⁺ 323 (3H-Benzoimidazol-5-yl)-(1-methyl-10-aza-tricyclo[7.2.1.0*2,7*]dodeca-2,4,6-trien-10- yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 318 [M + H]⁺ 324(3H-Benzoimidazol-5-yl)-(1-methyl-10-aza-tricyclo[7.4.1.0*2,7*]tetradeca-2,4,6-trien-10- yl)-methanone  

A Mass spectrum (ESI⁺): m/z = 346 [M + H]⁺ 325(3H-Benzoimidazol-5-yl)-(5,8,9,10-tetrahydro-6H-6,10-methano-pyrido[3,2- d]azocin-7-yl)-methanone  

  racemic mixture of the diastereomer shown A Mass spectrum (ESI⁺): m/z= 319 [M + H]⁺ 326 (3H-Benzoimidazol-5-yl)-(3,5,9-triaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-dien-9- yl)-methanone  

racemic mixture of the diastereomer shown A Mass spectrum (ESI⁺): m/z =308 [M + H]⁺ 327 (1H-Indol-3-yl)-(3,5,9-triaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-dien-9- yl)-methanone  

  racemic mixture of the diastereomer shown A Mass spectrum (ESI⁺): m/z= 307 [M + H]⁺ 328 (3H-Benzoimidazol-5-yl)-(4-methyl-3,5,9-triaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3- dien-9-yl)-methanone  

racemic mixture of the diastereomer shown A Mass spectrum (ESI⁺): m/z =322 [M + H]⁺ 329 (1H-Indol-3-yl)-(4-methyl-3,5,9-triaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-dien-9- yl)-methanone  

racemic mixture of the diastereomer shown A Mass spectrum (ESI⁺): m/z =321 [M + H]⁺ 330 (3H-Benzoimidazol-5-yl)-(7-hydroxy-3,3,4-trimethyl-2,3,4,4a,9,9a-hexahydro- indeno[2,1-b]pyridin-1-yl)-methanone 

A Mass spectrum (ESI⁺): m/z = 376 [M + H]⁺ 331(3,5-Difluoro-4-methoxy-phenyl)-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 386 [M + H]⁺ 332(3H-Benzoimidazol-5-yl)-[(2R,6R,11S)-6,11-dimethyl-8-(5-methyl-[1,3,4]oxadiazol-2-yl)-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 428 [M + H]⁺ 333(3H-Benzoimidazol-5-yl)-[(6R,10R,12S)-5,6,7,8,9,10-hexahydro-10,12-dimethyl-2-(5-methyl-pyrazin-2-yl)-6,10-methano-oxazolo[5,4-i][3]benzazocin-7-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 479 [M + H]⁺ 334(3H-Benzoimidazol-5-yl)-[(2R,6R,11S)-6,11dimethyl-8-[1,3,4]oxadiazol-2-yl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin 3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 414 [M + H]⁺ 335(3,5-Difluoro-4-hydroxy-phenyl)-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

J Mass spectrum (ESI⁺): m/z = 372 [M + H]⁺ 336(3H-Benzoimidazol-5-yl)-[(2R,6R,11S)-8-(4,5-dimethyl-4H-[1,2,4]triazol-3-yl)-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 441 [M + H]⁺ 337(3H-Benzoimidazol-5-yl)-[(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-2-[(R)-tetrahydrofuran-2-yl]-6,10-methano-oxazolo[4,5-i][3]benzazocin-7-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 471 [M + H]⁺ 338(3H-Benzoimidazol-5-yl)-[(6R,10S)-5,6,7,8,9,10-hexahydro-10,12,12-trimethyl-2-[(S)-tetrahydrofuran-2-yl]-6,10-methano-oxazolo[4,5-i][3]benzazocin-7-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 471 [M + H]⁺ 339[4-(2,2,2-Trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-[(2R,6S)-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 486 [M + H]⁺ 340(3H-Benzoimidazol-5-yl)-[(2R,6R,11S)-8-(1-hydroxy-1-methyl-ethyl)-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano- benzo[d]azocin-3-yl]-methanone  

  the compound is separated from compound Example 341 by HPLC onreversed phase A Mass spectrum (ESI⁺): m/z = 404 [M + H]⁺ 341(2R,6R,11S)-3-(3H-Benzoimidazole-5- carbonyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8- carboxylic acid methyl ester  

  the compound is separated from compound Example 340 by HPLC onreversed phase A Mass spectrum (ESI⁺): m/z = 404 [M + H]⁺ 3424-[(2R,6S)-6,11,11-Trimethyl-1,2,5,6- tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]- benzenesulfonamide  

A Mass spectrum (ESI⁺): m/z = 399 [M + H]⁺ 3433-[(2R,6S)-6,11,11-Trimethyl-1,2,5,6- tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]- benzenesulfonamide  

A Mass spectrum (ESI⁺): m/z = 399 [M + H]⁺ 344(3H-Benzoimidazol-5-yl)-[(2R,6S)-6,11,11-trimethyl-8-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone  

A Mass spectrum (ESI⁺): m/z = 404 [M + H]⁺ 3451-(3H-Benzoimidazole-5-carbonyl)- 1,2,3,4,9,9a-hexahydro-indeno[2,1-b]pyridine-4a-carboxylic acid methyl ester  

A Mass spectrum (ESI⁺): m/z = 376 [M + H]⁺

Some examples of formulations will now be described in which the term“active substance” denotes one or more compounds according to theinvention, including the salts thereof. In the case of one of thecombinations with one or additional active substances as describedpreviously, the term “active substance” also includes the additionalactive substances.

Example A

Tablets Containing 100 mg of Active Substance

Composition:

1 tablet contains:

active substance 100.0 mg  lactose 80.0 mg corn starch 34.0 mgpolyvinylpyrrolidone  4.0 mg magnesium stearate  2.0 mg 220.0 mg Method of Preparation:

The active substance, lactose and starch are mixed together anduniformly moistened with an aqueous solution of thepolyvinylpyrrolidone. After the moist composition has been screened (2.0mm mesh size) and dried in a rack-type drier at 50° C. it is screenedagain (1.5 mm mesh size) and the lubricant is added. The finishedmixture is compressed to form tablets.

-   -   Weight of tablet: 220 mg    -   Diameter: 10 mm, biplanar, facetted on both sides and notched on        one side.

Example B

Tablets Containing 150 mg of Active Substance

Composition:

1 tablet contains:

active substance 150.0 mg  powdered lactose 89.0 mg corn starch 40.0 mgcolloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0 mg Preparation:

The active substance mixed with lactose, corn starch and silica ismoistened with a 20% aqueous polyvinylpyrrolidone solution and passedthrough a screen with a mesh size of 1.5 mm. The granules, dried at 45°C., are passed through the same screen again and mixed with thespecified amount of magnesium stearate. Tablets are pressed from themixture.

-   -   Weight of tablet: 300 mg    -   die: 10 mm, flat

Example C

Hard Gelatine Capsules Containing 150 mg of Active Substance

Composition:

1 capsule contains:

active substance 150.0 mg corn starch (dried) approx. 180.0 mg lactose(powdered) approx. 87.0 mg magnesium stearate 3.0 mg approx. 420.0 mgPreparation:

The active substance is mixed with the excipients, passed through ascreen with a mesh size of 0.75 mm and homogeneously mixed using asuitable apparatus. The finished mixture is packed into size 1 hardgelatine capsules.

-   -   Capsule filling: approx. 320 mg    -   Capsule shell: size 1 hard gelatine capsule.

Example D

Suppositories Containing 150 mg of Active Substance

Composition:

1 suppository contains:

7active substance 150.0 mg polyethyleneglycol 1500 550.0 mgpolyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan monostearate840.0 mg 2,000.0 mg Preparation:

After the suppository mass has been melted the active substance ishomogeneously distributed therein and the melt is poured into chilledmoulds.

Example E

Ampoules Containing 10 mg Active Substance

Composition:

active substance 10.0 mg 0.01N hydrochloric acid q.s. double-distilledwater ad 2.0 mLPreparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with common salt, filtered sterile and transferred into 2mL ampoules.

Example F

Ampoules Containing 50 Ma of Active Substance

Composition:

active substance 50.0 mg 0.01N hydrochloric acid q.s. double-distilledwater ad 10.0 mLPreparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with common salt, filtered sterile and transferred into 10mL ampoules.

The invention claimed is:
 1. A compound of formula I

wherein R¹ denotes heteroaryl, selected from the group consisting ofindolyl, benzofuranyl, benzothiophenyl, quinolinyl, and isoquinolinyl,wherein 1 to 3 CH of said heteroaryl are optionally replaced by N,wherein the above-mentioned heteroaryl rings are optionally substitutedwith one R⁴, one to four identical or different R⁵ and/or one R⁶, andall heteroaryl rings are attached to the carbonyl group via a carbonatom, R² and R³ together with the double bond to which they are attacheddenote a benzo ring optionally substituted with R⁷, R⁸ and R⁹, or apyrido ring optionally substituted with R⁷, R⁸ and R⁹, R⁴ denotesfluorine, chlorine, bromine, iodine, C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, hydroxy, C₁₋₄-alkyloxy, nitro, amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)amino, pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl,piperidin-1-yl, 2-oxo-piperidin-1-yl, morpholin-4-yl,3-oxo-morpholin-4-yl, piperazin-1-yl, 2-oxo-piperazin-1-yl,3-oxo-piperazin-1-yl, 4-(C₁₋₃-alkyl)-piperazin-1-yl,4-(C₁₋₄-alkylcarbonyl)-piperazin-1-yl,4-(C₃₋₆-cycloalkylcarbonyl)-piperazin-1-yl,4-(C₁₋₄-alkyloxycarbonyl)-piperazin-1-yl,4-(C₁₋₄-alkylsulfonyl)-piperazin-1-yl,2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl, C₁₋₃-alkyl-carbonylamino,(het)aryl-carbonylamino, (het)aryl-C₁₋₃-alkyl-carbonylamino,C₁₋₃-alkyloxy-carbonylamino, aminocarbonylamino,C₁₋₃-alkyl-aminocarbonylamino, di-(C₁₋₃-alkyl)aminocarbonylamino,pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonylamino,morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino,4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonylamino, C₁₋₃-alkyl-sulfonylamino,aminosulfonylamino, C₁₋₃-alkylamino-sulfonylamino,di-(C₁₋₃-alkyl)amino-sulfonylamino, pyrrolidin-1-yl-sulfonylamino,piperidin-1-yl-sulfonylamino, morpholin-4-yl-sulfonylamino,piperazin-1-yl-sulfonylamino,4-(C₁₋₃-alkyl)-piperazin-1-yl-sulfonylamino,(C₁₋₃-alkyloxy-carbonylamino)carbonylamino, (het)arylsulfonylamino,(het)aryl-C₁₋₃-alkyl-sulfonylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-carbonylamino,N—(C₁₋₃-alkyl)-(het)arylcarbonylamino,N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkyl-carbonylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkyloxy-carbonyl-amino,N-(aminocarbonyl)-C₁₋₃-alkylamino,N—(C₁₋₃-alkyl-aminocarbonyl)-C₁₋₃-alkylamino,N-[di-(C₁₋₃-alkyl)aminocarbonyl]-C₁₋₃-alkylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-sulfonylamino,N—(C₁₋₃-alkyl)-(het)arylsulfonylamino,N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkyl-sulfonylamino,oxo-imidazolidin-1-yl, 2,4-dioxo-imidazolidin-1-yl,2,5-dioxo-imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl, wherein thenitrogen atom in position 3 of the aforementioned groups is optionallysubstituted with methyl or ethyl, cyano, carboxy,C₁₋₃-alkyloxy-carbonyl, aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, pyrrolidin-1-yl-carbonyl,piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl,piperazin-1-yl-carbonyl, 4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl,(het)arylaminocarbonyl, N—(C₁₋₃-alkyl)-(het)arylaminocarbonyl,(het)aryl-C₁₋₃-alkylaminocarbonyl,N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkylaminocarbonyl, C₁₋₃-alkyl-carbonyl,(het)aryl-carbonyl, carboxy-C₁₋₃-alkyl,C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyl, cyano-C₁₋₃-alkyl,aminocarbonyl-C₁₋₃-alkyl, C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl,pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl, piperidin-1-yl-carbonyl-C₁₋₃-alkyl,morpholin-4-yl-carbonyl-C₁₋₃-alkyl, piperazin-1-yl-carbonyl-C₁₋₃-alkyl,4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl-C₁₋₃-alkyl,carboxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyloxy,cyano-C₁₋₃-alkyloxy, aminocarbonyl-C₁₋₃-alkyloxy,C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyloxy,di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyloxy,pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl-oxy,piperidin-1-yl-carbonyl-C₁₋₃-alkyloxy,morpholin-4-yl-carbonyl-C₁₋₃-alkyl-oxy,piperazin-1-yl-carbonyl-C₁₋₃-alkyloxy,4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl-C₁₋₃-alkyloxy,hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-C₁₋₃-alkyl, amino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,pyrrolidin-1-yl-C₁₋₃-alkyl, 2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyl,piperidin-1-yl-C₁₋₃-alkyl, 2-oxo-piperidin-1-yl-C₁₋₃-alkyl,morpholin-4-yl-C₁₋₃-alkyl, 3-oxo-morpholin-4-yl-C₁₋₃-alkyl,piperazin-1-yl-C₁₋₃-alkyl, 2-oxo-piperazin -1-yl-C₁₋₃-alkyl,3-oxo-piperazin-1-yl-C₁₋₃-alkyl,4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyl,2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyl,3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyl,C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl, arylcarbonylamino-C₁₋₃-alkyl,hydroxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-C₁₋₃-alkyloxy,C₁₋₃-alkylsulfanyl-C₁₋₃-alkyloxy, C₁₋₃-alkylsulfinyl-C₁₋₃-alkyloxy,C₁₋₃-alkylsulfonyl-C₁₋₃-alkyloxy, amino-C₁₋₃-alkyloxy,C₁₋₃-alkylamino-C₁₋₃-alkyloxy, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyloxy,pyrrolidin-1-yl-C₁₋₃-alkyloxy, 2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyloxy,piperidin-1-yl-C₁₋₃-alkyloxy, 2-oxo-piperidin -1-yl-C₁₋₃-alkyloxy,morpholin-4-yl-C₁₋₃-alkyloxy, 3-oxo-morpholin-4-yl-C₁₋₃-alkyloxy,piperazin-1-yl-C₁₋₃-alkyloxy, 2-oxo-piperazin-1-yl-C₁₋₃-alkyloxy,3-oxo-piperazin -1-yl-C₁₋₃-alkyloxy,4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyloxy,2-oxo-4-(C₁₋₃-alkyl)-piperazin -1-yl-C₁₋₃-alkyloxy,3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyloxy, C₁₋₃-alkylsulfanyl,C₁₋₃-alkysulfinyl, C₁₋₃-alkylsulfonyl, C₁₋₃-alkylsulfonyloxy,(het)arylsulfonyl, (het)arylsulfonyloxy, trifluoromethylsulfanyl,trifluoromethylsulfinyl, trifluoromethylsulfonyl, aminosulfonyl,C₁₋₃-alkyl-aminosulfonyl, di-(C₁₋₃-alkyl)-aminosulfonyl,pyrrolidin-1-yl-sulfonyl, piperidin-1-yl-sulfonyl,morpholin-4-yl-sulfonyl, piperazin-1-yl-sulfonyl,4-(C₁₋₃-alkyl)-piperazin-1-yl-sulfonyl, difluoromethyl, trifluoromethyl,difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoro-1-hydroxyethyl,2,2,2-trifluoro-1-hydroxy-1-methylethyl,2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyloxy, C₃₋₆-cycloalkyl-C₁₋₃-alkyl,C₃₋₆-cycloalkyl-C₁₋₃-alkyloxy, (het)aryl, (het)aryloxy,(het)aryl-C₁₋₃-alkyl, (het)aryl-C₁₋₃-alkyloxy, (het)aryloxy-C₁₋₃-alkyl,or tetrahydrofuran-3-yl-oxy, tetrahydropyran-3-yl-oxy,tetrahydropyran-4-yl-oxy, tetrahydrofuranyl-C₁₋₃-alkyloxy,tetrahydropyranyl-C₁₋₃-alkyloxy, wherein the above-mentionedpyrrolidin-1-yl and piperidin-1-yl moieties are optionally substitutedwith one or two groups selected from methyl, ethyl, methoxymethyl,hydroxy or methoxy, and, wherein the above-mentioned piperazin-1-yl andmorpholin-4-yl moieties are optionally substituted with one or twogroups selected from methyl, ethyl or methoxymethyl, and wherein theabove-mentioned (het)aryl is phenyl, naphthyl, pyrrolyl, furanyl,thienyl, tetrazolyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl,quinolinyl, isoquinolinyl, or pyrrolyl, furanyl, thienyl, pyridyl inwhich 1 or 2 CH are replaced by N, or indolyl, benzofuranyl,benzothiophenyl, quinolinyl, isoquinolinyl in which 1 to 3 CH arereplaced by N, or 1,2-dihydro-2-oxo-pyridinyl,1,4-dihydro-4-oxo-pyridinyl, 2,3-dihydro-3-oxo-pyridazinyl,1,2,3,6-tetrahydro-3,6-dioxo-pyridazinyl, 1,2-dihydro-2-oxo-pyrimidinyl,3,4-dihydro-4-oxo-pyrimidinyl, 1,2,3,4-tetrahydro-2,4-dioxo-pyrimidinyl,1,2-dihydro -2-oxo-pyrazinyl, 1,2,3,4-tetrahydro-2,3-dioxo-pyrazinyl,2,3-dihydro-2-oxo-indolyl, 2,3-dihydrobenzofuranyl,2,3-dihydro-2-oxo-1H-benzimidazolyl, 2,3-dihydro-2-oxo-benzoxazolyl,1,2-dihydro-2-oxo-quinolinyl, 1,4-dihydro-4-oxo-quinolinyl,1,2-dihydro-1-oxo-isoquinolinyl, 1,4-dihydro-4-oxo-cinnolinyl,1,2-dihydro-2-oxo-quinazolinyl, 1,4-dihydro-4-oxo-quinazolinyl,1,2,3,4-tetrahydro-2,4-dioxo-quinazolinyl,1,2-dihydro-2-oxoquinoxalinyl, 1,2,3,4-tetrahydro-3-oxo-quinoxalinyl,1,2,3,4-tetrahydro-2,3-dioxo-quinoxalinyl,1,2-dihydro-1-oxo-phthalazinyl,1,2,3,4-tetrahydro-1,4-dioxo-phthalazinyl, chromanyl, coumarinyl,2,3-dihydro-benzo [1,4]dioxinyl,3,4-dihydro-3-oxo-2H-benzo[1,4]oxazinyl, and wherein the above-mentioned(het)aryl groups are optionally substituted with one or two R¹⁰ whichmay be identical or different, R⁵ and R⁶, which may be identical ordifferent, denote halogen, C₁₋₃-alkyl, C₂₋₃-alkynyl, trifluormethyl,hydroxy, C₁₋₃-alkyloxy, cyano, or R⁵ together with R⁶, if bound toadjacent carbon atoms, may additionally be methylenedioxy,difluoromethylenedioxy, ethylenedioxy, C₃₋₅-alkylene, R⁷ denotesfluorine, chlorine, bromine, iodine, C₁₋₄-alkyl, hydroxy, C₁₋₄-alkyloxy,nitro, amino, C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)amino, pyrrolidin-1-yl,2-oxo-pyrrolidin-1-yl, piperidin-1-yl, 2-oxo-piperidin-1-yl,morpholin-4-yl, 3-oxo-morpholin-4-yl, piperazin-1-yl,2-oxo-piperazin-1-yl, 3-oxo-piperazin-1-yl,4-(C₁₋₄-alkyl)-pi-perazin-1-yl, 4-(C₁₋₄-alkylcarbonyl)-piperazin-1-yl,4-(C₃₋₆-cycloalkylcarbonyl)-piperazin-1-yl,4-(C₁₋₄-alkyloxycarbonyl)-piperazin-1-yl,4-(C₁₋₄-alkylsulfonyl)-piperazin-1-yl,2-oxo-4-(C₁₋₄-alkyl)-piperazin-1-yl,3-oxo-4-(C₁₋₄-alkyl)-piperazin-1-yl, C₁₋₄-alkyl-carbonylamino,(het)aryl-carbonylamino, (het)aryl-C₁₋₄-alkyl-carbonylamino,C₁₋-alkyloxy-carbonylamino, aminocarbonylamino,C₁₋₄-alkyl-aminocarbonylamino, di -(C₁₋₄-alkyl)aminocarbonylamino,pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonylamino,morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino,4-(C₁₋₄-alkyl)-piperazin-1-yl-carbonylamino, C₁₋₄-alkyl-sulfonylamino,aminosulfonylamino, C₁₋₄-alkylamino-sulfonylamino,di-(C₁₋₄-alkyl)amino-sulfonylamino, pyrrolidin-1-yl-sulfonylamino,piperidin-1-yl-sulfonylamino, morpholin-4-yl-sulfonylamino, piperazin-1-yl-sulfonylamino, 4-(C₁₋₄-alkyl)-piperazin-1-yl-sulfonylamino,(C₁₋₄-alkyloxy-carbonylamino)carbonylamino, (het)arylsulfonylamino,(het)aryl-C₁₋₄-alkyl-sulfonylamino,N—(C₁₋₄-alkyl)-C₁₋₄-alkyl-carbonylamino,N—(C₁₋₄-alkyl)-(het)arylcarbonylamino,N—(C₁₋₄-alkyl)-(het)aryl-C₁₋₄-alkyl-carbonylamino,N—(C₁₋₄-alkyl)-C₁₋₄-alkyloxy-carbonyl-amino,N-(aminocarbonyl)-C₁₋₄-alkylamino,N—(C₁₋₄-alkyl-aminocarbonyl)-C₁₋₄-alkylamino,N-[di-(C₁₋₄-alkyl)aminocarbonyl]-C₁₋₄-alkylamino,N—(C₁₋₄-alkyl)-C₁₋₄-alkyl-sulfonylamino,N—(C₁₋₄-alkyl)-(het)arylsulfonylamino,N—(C₁₋₄-alkyl)-(het)aryl-C₁₋₄-alkyl-sulfonylamino,oxo-imidazolidin-1-yl, 2,4-dioxo-imidazolidin-1-yl,2,5-dioxo-imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl, wherein thenitrogen atom in position 3 of the aforementioned groups is optionallysubstituted with methyl or ethyl, cyano, (hydroxyimino)aminomethyl,(C₁₋₄-alkyloxyimino)aminomethyl, carboxy, C₁₋₄-alkyloxy-carbonyl,aminocarbonyl, C₁₋₄-alkyl-aminocarbonyl, di-(C₁₋₄-alkyl)-amino-carbonyl,pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl,morpholin-4-yl-carbonyl, piperazin-1-yl-carbonyl,4-(C₁₋₄-alkyl)-piperazin-1-yl-carbonyl, C₁₋₄-alkyl-carbonyl,(het)aryl-carbonyl, carboxy-C₁₋₄-alkyl,C₁₋₄-alkyloxy-carbonyl-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl,aminocarbonyl-C₁₋₄-alkyl, C₁₋₄-alkyl-aminocarbonyl-C₁₋₄-alkyl,di-(C₁₋₄-alkyl)-aminocarbonyl-C₁₋₄-alkyl,pyrrolidin-1-yl-carbonyl-C₁₋₄-alkyl, piperidin-1-yl-carbonyl-C₁₋₄-alkyl,morpholin-4-yl-carbonyl-C₁₋₄-alkyl, piperazin-1-yl-carbonyl-C₁₋₄-alkyl,4-(C₁₋₄-alkyl)-piperazin-1-yl-carbonyl-C₁₋₄-alkyl,carboxy-C₁₋₄-alkyloxy, C₁₋₄-alkyloxy-carbonyl-C₁₋₄-alkyloxy,cyano-C₁₋₄-alkyloxy, amino-carbonyl-C₁₋₄-alkyloxy,C₁₋₄-alkyl-aminocarbonyl-C₁₋₄-alkyloxy,di-(C₁₋₄-alkyl)-amino-carbonyl-C₁₋₄-alkyloxy,pyrrolidin-1-yl-carbonyl-C₁₋₄-alkyl-oxy,piperidin-1-yl-carbonyl-C₁₋₄-alkyloxy,morpholin-4-yl-carbonyl-C₁₋₄-alkyl-oxy,piperazin-1-yl-carbonyl-C₁₋₄-alkyloxy,4-(C₁₋₄-alkyl)-piperazin-1-yl-carbonyl-C₁₋₄-alkyloxy,hydroxy-C₁₋₄-alkyl, C₁₋₄-alkyloxy-C₁₋₄-alkyl, amino-C₁₋₄-alkyl,C₁₋₄-alkylamino-C₁₋₄-alkyl, di-(C₁₋₄-alkyl)-amino-C₁₋₄-alkyl,pyrrolidin-1-yl-C₁₋₄-alkyl, C₁₋₄-alkylcarbonyl-amino-C₁₋₄-alkyl,N—(C₁₋₄-alkyl)-C₁₋₄-alkylcarbonyl-amino-C₁₋₄-alkyl,2-oxo-pyrrolidin-1-yl-C₁₋₄-alkyl, piperidin-1-yl-C₁₋₄-alkyl,2-oxo-piperidin-1-yl-C₁₋₄-alkyl, morpholin-4-yl-C₁₋₄-alkyl,3-oxo-morpholin-4-yl-C₁₋₄-alkyl, piperazin-1-yl-C₁₋₄-alkyl,2-oxo-piperazin-1-yl-C₁₋₄-alkyl, 3-oxo-piperazin-1-yl-C₁₋₄-alkyl,4-(C₁₋₄-alkyl)-piperazin -1-yl-C₁₋₄-alkyl,2-oxo-4-(C₁₋₄-alkyl)-piperazin-1-yl-C₁₋₄-alkyl,3-oxo-4-(C₁₋₄-alkyl)-piperazin-1-yl-C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyloxy,C₁₋₄-alkyloxy-C₁₋₄-alkyloxy, C₁₋₄-alkylsulfanyl-C₁₋₄-alkyloxy,C₁₋₄-alkylsulfinyl-C₁₋₄-alkyloxy, C₁₋₄-alkylsulfonyl-C₁₋₄-alkyloxy,amino-C₁₋₄-alkyloxy, C₁₋₄-alkylamino-C₁₋₄-alkyloxy,di-(C₁₋₄-alkyl)-amino-C₁₋₄-alkyloxy, pyrrolidin-1-yl-C₁₋₄-alkyloxy,2-oxo-pyrrolidin-1-yl-C₁₋₄-alkyloxy, piperidin-1-yl-C₁₋₄-alkyloxy,2-oxo-piperidin -1-yl-C₁₋₄-alkyloxy, morpholin-4-yl-C₁₋₄-alkyloxy,3-oxo-morpholin-4-yl-C₁₋₄-alkyloxy, piperazin-1-yl-C₁₋₄-alkyloxy,2-oxo-piperazin-1-yl-C₁₋₄-alkyloxy, 3-oxo-piperazin -1-yl-C₁₋₄-alkyloxy,4-(C₁₋₄-alkyl)-piperazin-1-yl-C₁₋₄-alkyloxy,2-oxo-4-(C₁₋₄-alkyl)-piperazin-1-yl-C₁₋₄-alkyloxy,3-oxo-4-(C₁₋₄-alkyl)-piperazin-1-yl-C₁₋₄-alkyloxy, C₁₋₄-alkylsulfanyl,C₁₋₄-alkysulfinyl, C₁₋₄-alkylsulfonyl, C₁₋₄-alkylsulfonyloxy,(het)arylsulfonyl, (het)arylsulfonyloxy, trifluoromethylsulfanyl,trifluoromethylsulfinyl, trifluoromethylsulfonyl,C₃₋₆-cycloalkylsulfanyl, C₃₋₆-cycloalkylsulfinyl,C₃₋₆-cycloalkylsulfonyl, C₃₋₆-cycloalkyl-C₁₋₃-alkylsulfanyl,C₃₋₆-cycloalkyl-C₁₋₃-alkylsulfinyl, C₃₋₆-cycloalkyl-C₁₋₃-alkylsulfonyl,aminosulfonyl, C₁₋₄-alkyl-aminosulfonyl, di-(C₁₋₄-alkyl)-aminosulfonyl,pyrrolidin-1-yl-sulfonyl, piperidin-1-yl-sulfonyl,morpholin-4-yl-sulfonyl, piperazin-1-yl-sulfonyl,4-(C₁₋₄-alkyl)-piperazin-1-yl-sulfonyl, difluoromethyl, trifluoromethyl,difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoro-1-hydroxyethyl,2,2,2-trifluoro-1-hydroxy-1-methylethyl,2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyloxy, hydroxy-C₄₋₆-cycloalkyl,C₁₋₃-alkyloxy-C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyl,C₃₋₆-cycloalkyl-C₁₋₃-alkyloxy, (het)aryl, (het)aryloxy,(het)aryl-C₁₋₃-alkyl, (het)aryl-C₁₋₃-alkyloxy, (het)aryloxy-C₁₋₃-alkyl,or tetrahydrofuran-3-yl-oxy, tetrahydropyran-3-yl-oxy,tetrahydropyran-4-yl-oxy, tetrahydrofuranyl-C₁₋₃-alkyloxy,tetrahydropyranyl-C₁₋₃-alkyloxy, wherein the above-mentioned (het)arylis defined as described for R⁴ hereinbefore, R⁸ and R⁹, which may beidentical or different, are halogen, C₁₋₃-alkyl, trifluormethyl,hydroxy, C₁₋₃-alkyloxy, cyano, or R⁸ together with R⁹, if bound toadjacent carbon atoms, may additionally be methylenedioxy,difluoromethylenedioxy, ethylenedioxy, C₃₋₅-alkylene, R¹⁰ is R^(10′) orR^(10″) and R^(10′) denotes halogen, C₁₋₃-alkyl, difluoromethyl,trifluoromethyl, cyano, nitro, amino, acetylamino, methylsulfonylamino,carboxy, C₁₋₄-alkyloxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, aminosulfonyl, methylsulfanyl,methylsulfinyl, methylsulfonyl, hydroxy, C₁₋₃-alkyloxy, difluoromethoxy,or trifluoromethoxy, R^(10″) denotes pyrrolyl, furanyl, thienyl,pyridyl, wherein in any of these groups 1 or 2 CH optionally arereplaced by N atoms, or indolyl, benzofuranyl, benzothiophenyl,quinolinyl, isoquinolinyl, wherein in any of these groups 1 to 3 CHoptionally are replaced by N atoms, or phenyl, naphthyl, tetrazolyl,1,2-dihydro-2-oxo-pyridinyl, 1,4-dihydro-4-oxo-pyridinyl,2,3-dihydro-3-oxo-pyridazinyl, 1,2,3,6-tetrahydro-3,6-dioxo-pyridazinyl,1,2-dihydro-2-oxo-pyrimidinyl, 3,4-dihydro-4-oxo-pyrimidinyl,1,2,3,4-tetrahydro-2,4-dioxo-pyrimidinyl, 1,2-dihydro-2-oxo-pyrazinyl,1,2,3,4-tetrahydro-2,3-dioxo-pyrazinyl, 2,3-dihydro-2-oxo-indolyl,2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxo-1H-benzimidazolyl,2,3-dihydro-2-oxo-benzoxazolyl, 1,2-dihydro-2-oxo-quinolinyl,1,4-dihydro-4-oxo-quinolinyl, 1,2-dihydro-1-oxo-isoquinolinyl,1,4-dihydro-4-oxo-cinnolinyl, 1,2-dihydro-2-oxo-quinazolinyl,1,4-dihydro-4-oxo-quinazolinyl,1,2,3,4-tetrahydro-2,4-dioxo-quinazolinyl,1,2-dihydro-2-oxoquinoxalinyl, 1,2,3,4-tetrahydro-3-oxo-quinoxalinyl,1,2,3,4-tetrahydro-2,3-dioxo-quinoxalinyl,1,2-dihydro-1-oxo-phthalazinyl,1,2,3,4-tetrahydro-1,4-dioxo-phthalazinyl, chromanyl, coumarinyl,2,3-dihydro-benzo[1,4]dioxinyl, or3,4-dihydro-3-oxo-2H-benzo[1,4]oxazinyl, and wherein any of the groupsmentioned hereinbefore under R^(10″) optionally are substitutedindependently with one or two groups selected from halogen, C₁₋₃-alkyl,difluoromethyl, trifluoromethyl, cyano, nitro, amino, acetylamino,methylsulfonylamino, carboxy, C₁₋₄-alkyl-oxycarbonyl, aminocarbonyl,C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl, aminosulfonyl,methylsulfanyl, methylsulfinyl, methylsulfonyl, hydroxy, C₁₋₃-alkyloxy,difluoromethoxy, and trifluoromethoxy, X denotes CH, m, n, o are each 1,and wherein the bicyclic core structure of formula I is optionallysubstituted independently with R¹¹ to R¹⁴, wherein R¹¹ denotes fluorine,C₁₋₄-alkyl, (het)aryl, hydroxy, C₁₋₄-alkyloxy, cyano, carboxy,C₁₋₄-alkyloxycarbonyl, aminocarbonyl, C₁₋₄-alkylamino-carbonyl,di-(C₁₋₄-alkyl)-aminocarbonyl, hydroxy-C₁₋₄-alkyl orC₁₋₃-alkyloxy-C₁₋₄-alkyl, wherein (het)aryl is as described for R⁴hereinbefore, R¹² denotes fluorine or C₁₋₄-alkyl, and R¹³ and R¹⁴, whichmay be identical or different, denote C₁₋₄-alkyl, and wherein theabove-mentioned alkyl or alkylene moieties are branched or unbranched,or a tautomer thereof, stereoisomer thereof, mixture thereof, or a saltthereof.
 2. A compound according to claim 1, wherein R¹ denotesheteroaryl, selected from the group consisting of indolyl, benzofuranyl,benzothiophenyl, quinolinyl, or isoquinolinyl, wherein 1 to 3 CH of saidheteroaryls are optionally replaced by N, and each of said heteroarylsare independently substituted with one R⁴, one to four identical ordifferent R⁵, and/or one R⁶, R² and R³, together with the double bond towhich they are attached, denote a benzo or pyrido ring optionally bothindependently substituted with R⁷, R⁸ and R⁹, R⁴ denotes fluorine,chlorine, bromine, C₁₋₄-alkyl, hydroxyl, C₁₋₄-alkyloxy, nitro, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino, pyrrolidin-1-yl,2-oxo-pyrrolidin-1-yl, piperidin-1-yl, 2-oxo-piperidin-1-yl,morpholin-4-yl, 3-oxo-morpholin-4-yl, piperazin-1-yl,2-oxo-piperazin-1-yl, 3-oxo-piperazin-1-yl, 4-(C₁₋₃-alkyl)-piperazin-1-yl, 4-(C ₁₋₄-alkylcarbonyl)-piperazin-1-yl,4-(C₃₋₆-cycloalkylcarbonyl)-piperazin-1-yl,4-(C₁₋₄-alkyloxycarbonyl)-piperazin-1-yl,4-(C₁₋₄-alkylsulfonyl)-piperazin-1-yl,2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl, C₁₋₃-alkyl-carbonylamino,(het)arylcarbonylamino, (het)aryl-C₁₋₃-alkyl-carbonylamino,C₁₋₃-alkyloxy-carbonylamino, aminocarbonylamino,C₁₋₃-alkyl-aminocarbonylamino, di-(C₁₋₃-alkyl)aminocarbonylamino,pyrrolidin-1-yl-carbonylamino, piperidin-1-yl -carbonylamino,morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino,4-(C₁₋₃-alkyl) -piperazin-1-yl-carbonylamino, C₁₋₃-alkyl-sulfonylamino,(het)arylsulfonylamino, (het)aryl-C₁₋₃-alkyl-sulfonylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-carbonylamino,N—(C₁₋₃-alkyl)-(het)arylcarbonylamino, N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkyl-carbonylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkyloxy-carbonyl -amino,N—(aminocarbonyl)-C₁₋₃-alkylamino,N—(C₁₋₃-alkyl-aminocarbonyl)-C₁₋₃-alkylamino,N—[di-(C₁₋₃-alkyl)aminocarbonyl]-C₁₋₃-alkylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-sulfonylamino,N—(C₁₋₃-alkyl)-(het)arylsulfonylamino, N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkyl-sulfonylamino, oxo-imidazolidin-1-yl,2,4-dioxo-imidazolidin-1-yl, 2,5-dioxo-imidazolidin-1-yl,2-oxo-hexahydropyrimidin-1-yl, wherein the nitrogen atom in position 3of the aforementioned groups is optionally substituted with methyl orethyl, cyano, carboxy, C₁₋₃-alkyloxy-carbonyl, aminocarbonyl,C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl) -aminocarbonyl,pyrrolidin-1-yl-carbonyl, 2-(methoxymethyl)-pyrrolidin-1-yl-carbonyl, 3-(methoxymethyl)-pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl,morpholin-4-yl-carbonyl, piperazin-1-yl-carbonyl,4-(C₁₋₃-alkyl)-piperazin-1-yl -carbonyl, (het)arylaminocarbonyl,N—(C₁₋₃-alkyl)-(het)arylaminocarbonyl,(het)aryl-C₁₋₃-alkylaminocarbonyl,N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkylaminocarbonyl, C₁₋₃-alkyl-carbonyl,(het)aryl-carbonyl, carboxy-C₁₋₃-alkyl,C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyl, cyano-C₁₋₃-alkyl, aminocarbonyl-C₁₋₃-alkyl, C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl,pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl, piperidin-1-yl-carbonyl-C₁₋₃-alkyl,morpholin-4-yl-carbonyl-C₁₋₃-alkyl, piperazin-1-yl-carbonyl-C₁₋₃-alkyl,4-(C₁₋₃-alkyl)-piperazin -1-yl-carbonyl-C₁₋₃-alkyl,carboxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyloxy,cyano-C₁₋₃-alkyloxy, aminocarbonyl-C₁₋₃-alkyloxy,C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyloxy, di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyloxy, pyrrolidin-1 -yl-carbonyl-C₁₋₃-alkyl-oxy,piperidin-1-yl-carbonyl-C₁₋₃-alkyloxy,morpholin-4-yl-carbonyl-C₁₋₃-alkyl-oxy, piperazin-1-yl-carbonyl-C₁₋₃-alkyloxy, 4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl-C₁₋₃-alkyloxy, hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-C₁₋₃-alkyl,amino-C₁₋₃-alkyl, C₁₋₃-alkylamino-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl, pyrrolidin-1-yl-C₁₋₃-alkyl,2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyl, piperidin-1-yl-C₁₋₃-alkyl,2-oxo-piperidin-1-yl-C₁₋₃-alkyl, morpholin-4-yl-C₁₋₃ -alkyl,(methyl-morpholin-4-yl)-C₁₋₃-alkyl,(dimethyl-morpholin-4-yl)-C₁₋₃-alkyl, 3-oxo-morpholin-4-yl-C₁₋₃-alkyl,piperazin-1-yl-C₁₋₃-alkyl, 2-oxo-piperazin-1-yl-C₁₋₃-alkyl,3-oxo-piperazin-1-yl-C₁₋₃-alkyl,4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyl,2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyl,2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyl,C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl, (het)arylcarbonylamino-C₁₋₃-alkyl,hydroxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-C₁₋₃-alkyloxy,C₁₋₃-alkylsulfanyl-C₁₋₃-alkyloxy, C₁₋₃-alkylsulfinyl-C₁₋₃-alkyloxy,C₁₋₃-alkylsulfonyl-C₁₋₃-alkyloxy, amino-C₁₋₃-alkyloxy,C₁₋₃-alkylamino-C₁₋₃-alkyloxy, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyloxy,pyrrolidin-1-yl-C₁₋₃-alkyloxy, 2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyloxy,piperidin-1-yl-C₁₋₃-alkyloxy, 2-oxo-piperidin-1-yl-C₁₋₃-alkyloxy,morpholin-4-yl-C₁₋₃-alkyloxy, 3-oxo-morpholin-4-yl-C₁₋₃-alkyloxy,piperazin-1-yl-C₁₋₃-alkyloxy, 2-oxo-piperazin-1-yl-C₁₋₃-alkyloxy,3-oxo-piperazin-1-yl-C₁₋₃-alkyloxy,4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyloxy,2-oxo-4-(C₁₋₃-alkyl)-piperazin-1 -yl-C₁₋₃-alkyloxy,3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyloxy, C₁₋₃-alkylsulfanyl,C₁₋₃-alkysulfinyl, C₁₋₃-alkylsulfonyl, (het)arylsulfonyl, aminosulfonyl,C₁₋₃-alkyl-aminosulfonyl, di-(C₁₋₃-alkyl)-aminosulfonyl,pyrrolidin-1-yl-sulfonyl, piperidin-1-yl-sulfonyl,morpholin-4-yl-sulfonyl, piperazin-1-yl-sulfonyl,4-(C₁₋₃-alkyl)-piperazin-1-yl-sulfonyl, difluoromethyl, trifluoromethyl,difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoro-1-hydroxyethyl,2,2,2-trifluoro-1-hydroxy-1-methylethyl,2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyloxy, C₃₋₆-cycloalkyl-C₁₋₃-alkyl,C₃₋₆-cycloalkyl-C₁₋₃-alkyloxy, (het)aryl, (het)aryloxy,(het)aryl-C₁₋₃-alkyl, (het)aryl-C₁₋₃-alkyloxy, (het)aryloxy-C₁₋₃ -alkyl,or tetrahydrofuran-3-yl-oxy, tetrahydropyran-3-yl-oxy,tetrahydropyran-4-yl-oxy, tetra-hydrofuranyl-C₁₋₃-alkyloxy,tetrahydropyranyl-C₁₋₃-alkyloxy, wherein the above-mentioned (het)arylgroups are phenyl, naphthyl, or pyrrolyl, furanyl, thienyl, pyridyl,indolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, orpyrrolyl, furanyl, thienyl, pyridyl wherein 1 or 2 CH are replaced by N,or indolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinylwherein 1 to 3 CH are replaced by N, or 1,2-dihydro-2-oxo-pyridinyl,1,4-dihydro-4-oxo-pyridinyl, 2,3-dihydro-3-oxo-pyridazinyl,1,2,3,6-tetrahydro-3,6-dioxo-pyridazinyl, 1,2-dihydro-2-oxo-pyrimidinyl,3,4-dihydro-4-oxo-pyrimidinyl, 1,2,3,4-tetrahydro-2,4-dioxo-pyrimidinyl,1,2-dihydro -2-oxo-pyrazinyl, 1,2,3,4-tetrahydro-2,3-dioxo-pyrazinyl,2,3-dihydro-2-oxo-indolyl, 2,3-dihydrobenzofuranyl,2,3-dihydro-2-oxo-1H-benzimidazolyl, 2,3-dihydro-2-oxo-benzoxazolyl,1,2-dihydro-2-oxo-quinolinyl, 1,4-dihydro-4-oxo-quinolinyl,1,2-dihydro-1-oxo-isoquinolinyl, 1,4-dihydro-4-oxo-cinnolinyl,1,2-dihydro-2-oxo-quinazolinyl, 1,4-dihydro-4-oxo-quinazolinyl,1,2,3,4-tetrahydro-2,4-dioxo-quinazolinyl,1,2-dihydro-2-oxoquinoxalinyl, 1,2,3,4-tetrahydro-3-oxo-quinoxalinyl,1,2,3,4-tetrahydro-2,3-dioxo-quinoxalinyl,1,2-dihydro-1-oxo-phthalazinyl,1,2,3,4-tetrahydro-1,4-dioxo-phthalazinyl, chromanyl, coumarinyl,2,3-dihydro- benzo[1,4]dioxinyl, or3,4-dihydro-3-oxo-2H-benzo[1,4]oxazinyl, and wherein any of the groupsmentioned for the (het)aryl groups are optionally substituted with oneor two R¹⁰ which may be identical or different, R⁵ and R⁶ areindependently selected from among fluorine, chlorine, bromine,C₁₋₃-alkyl, C₂₋₃ -alkynyl, trifluoromethyl, hydroxy, C₁₋₃-alkyloxy, andcyano, or if R⁵ and R⁶ are bound to adjacent carbon atoms they togethermay additionally denote methylenedioxy, difluoromethylenedioxy,ethylenedioxy or C₃₋₅-alkylene, R⁷ denotes fluorine, chlorine,C₁₋₄-alkyl, hydroxy, C₁₋₄-alkyloxy, nitro, amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)amino, pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl,piperidin-1-yl, 2-oxo-piperidin-1-yl, morpholin-4-yl,3-oxo-morpholin-4-yl, 3-oxo-piperazin -1-yl,4-(C₁₋₄-alkylcarbonyl)-piperazin-1-yl, C₁₋₃-alkyl-carbonylamino,(het)aryl-carbonylamino, C₁₋₃-alkyloxy-carbonylamino,C₁₋₃-alkyl-aminocarbonylamino, di-(C₁₋₃-alkyl)aminocarbonylamino,pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbonylamino,morpholin-4-yl-carbonylamino, C₁₋₃-alkyl-sulfonylamino,C₁₋₃-alkylamino-sulfonylamino, di-(C₁₋₃-alkyl)amino-sulfonylamino,pyrrolidin-1-yl-sulfonylamino, piperidin-1-yl-sulfonylamino,morpholin-4-yl-sulfonylamino, (het)arylsulfonylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-carbonylamino,N—(C₁₋₃-alkyl)-(het)arylcarbonylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkyloxy-carbonylamino,N—(C₁₋₃-alkyl-aminocarbonyl)-C₁₋₃-alkylamino,N-[di-(C₁₋₃-alkyl)aminocarbonyl]-C₁₋₃-alkylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-sulfonylamino,N—(C₁₋₃-alkyl)-(het)arylsulfonylamino, cyano, (hydroxyimino)aminomethyl,(C₁₋₃-alkyloxyimino)aminomethyl, carboxy, C₁₋₃-alkyloxy-carbonyl,aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-amino-carbonyl,pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl,morpholin-4-yl-carbonyl, C₁₋₃-alkyl-carbonyl, (het)aryl-carbonyl,carboxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyl, cyano-C₁₋₃-alkyl,ami-nocarbonyl-C₁₋₃-alkyl, C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl,pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl, piperidin-1-yl-carbonyl-C₁₋₃-alkyl, morpholin-4-yl-carbonyl-C₁₋₃-alkyl, carboxy-C₁₋₃-alkyloxy,C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyloxy, cyano-C₁₋₃-alkyloxy,aminocarbonyl-C₁₋₃-alkyloxy, C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyloxy,di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyloxy,pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl-oxy,piperidin-1-yl-carbonyl-C₁₋₃-alkyloxy,morpholin-4-yl-carbonyl-C₁₋₃-alkyl-oxy, hydroxy-C₁₋₄-alkyl,C₁₋₃-alkyloxy-C₁₋₄-alkyl, amino-C₁₋₃-alkyl, C₁₋₃-alkylamino-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl, pyrrolidin-1-yl-C₁₋₃-alkyl,2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyl, C₁₋₄-alkylcarbonyl-amino-C₁₋₃-alkyl,N—(C₁₋₃-alkyl)-C₁₋₄-alkylcarbonyl-amino-C₁₋₃-alkyl,2-oxo-piperidin-1-yl-C₁₋₃-alkyl, 3-oxo-morpholin-4-yl-C₁₋₃-alkyl,hydroxy-C₁₋₄-alkyloxy, C₁₋₄-alkyloxy-C₁₋₄-alkyloxy,C₁₋₃-alkylsulfinyl-C₁₋₃-alkyloxy, C₁₋₃-alkylsulfonyl-C₁₋₃-alkyloxy,di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyloxy, 2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyloxy, 2-oxo-piperidin-1-yl-C₁₋₃-alkyloxy,morpholin-4-yl-C₁₋₃-alkyloxy, 3-oxo-morpholin-4-yl-C₁₋₃-alkyloxy,C₁₋₄-alkylsulfanyl, C₁₋₄-alkysulfinyl, C₁₋₄-alkylsulfonyl,(het)arylsulfonyl, C₃₋₆-cycloalkylsulfanyl, C₃₋₆-cycloalkylsulfinyl,C₃₋₆-cycloalkylsulfonyl, aminosulfonyl, C₁₋₃-alkyl-aminosulfonyl,di-(C₁₋₃-alkyl)-aminosulfonyl, pyrrolidin-1-yl-sulfonyl,piperidin-1-yl-sulfonyl, morpholin-4-yl-sulfonyl, difluoromethyl,trifluoromethyl, difluoromethoxy, trifluoromethoxy, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyloxy, C₃₋₆-cycloalkyl-C₁₋₃-alkyl, C₃₋₆-cycloalkylC₁₋₃-alkoxy, (het)aryl, (het)aryloxy, (het)aryl-C₁₋₃-alkyl,(het)aryl-C₁₋₃-alkyloxy, (het)aryloxy-C₁₋₃ -alkyl, ortetrahydrofuran-3-yl-oxy, tetrahydropyran-3-yl-oxy,tetrahydropyran-4-yl-oxy, tetra-hydrofuranyl-C₁₋₃-alkyloxy, ortetrahydropyranyl-C₁₋₃-alkyloxy, wherein the above-mentioned (het)arylgroups are defined as described hereinbefore under R⁴, R⁸ and R⁹, whichmay be identical or different, denote fluorine, chlorine, bromine,C₁₋₃-alkyl, trifluoromethyl, hydroxy, C₁₋₃-alkyloxy or cyano, or if R⁸and R⁹ are bound to adjacent carbon atoms they together may additionallydenote methylenedioxy, difluoromethylenedioxy, ethylenedioxy,C₃₋₅-alkylene, R¹⁰ denotes fluorine, chlorine, bromine, C₁₋₃-alkyl,difluoromethyl, trifluoromethyl, cyano, nitro, amino, acetylamino,methylsulfonylamino, carboxy, C₁₋₄-alkyloxycarbonyl, aminocarbonyl,C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl, aminosulfonyl,methylsulfanyl, methylsulfinyl, methylsulfonyl, phenyl, hydroxy,C₁₋₃-alkyloxy, difluorome -thoxy, or trifluoromethoxy, R¹¹ denotesfluorine, C₁₋₃-alkyl, phenyl, hydroxy, C₁₋₃-alkyloxy, cyano, carboxy,C₁₋₄-alkyloxycarbonyl, aminocarbonyl, C₁₋₄-alkylamino-carbonyl,di-(C₁₋₄-alkyl)-aminocarbonyl, hydroxy-C₁₋₄-alkyl orC₁₋₃-alkyloxy-C₁₋₄-alkyl, R¹² denotes fluorine, hydrogen or C₁₋₃-alkyl;and R¹³ and R¹⁴, which may be identical or different, denote C₁₋₃-alkyl,or a tautomer, stereoisomer, mixture thereof or salt thereof.
 3. Acompound according to claim 1, wherein R¹ denotes indolyl, quinolinyl,or isoquinolinyl, wherein any of these groups optionally areindependently substituted with one R⁴, one to four identical ordifferent R⁵, and/or one R⁶, R² and R³, together with the double bond towhich they are attached, denote a benzo or pyrido ring, optionally bothindependently substituted with R⁷, R⁸ and R⁹, R⁴ denotes fluorine,chlorine, bromine, C₁₋₄-alkyl, hydroxy, C₁₋₄-alkyloxy, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino, pyrrolidin-1-yl,2-oxo-pyrrolidin-1-yl, piperidin-1-yl, 2-oxo-piperidin-1 -yl,morpholin-4-yl, 3-oxo-morpholin-4-yl, piperazin-1 -yl, 2-oxo-piperazin-1-yl, 3-oxo-piperazin-1-yl, 4-(C₁₋₃-alkyl)-piperazin-1 -yl, 4-(C₁₋₄-alkyl-carbonyl)-piperazin-1-yl, 4-(C₃₋₆-cycloalkylcarbonyl)-piperazin-1-yl,4-(C₁₋₄-alkyloxy -carbonyl)-piperazin-1-yl,4-(C₁₋₄-alkylsulfonyl)-piperazin-1-yl, 2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl, 3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,C₁₋₃-alkyl-carbonylamino, (het)arylcarbonylamino,(het)aryl-C₁₋₃-alkyl-carbonylamino, C₁₋₃ -alkyloxy-carbonylamino,aminocarbonylamino, C₁₋₃-alkyl-aminocarbonylamino,di-(C₁₋₃-alkyl)aminocarbonylamino, pyrrolidin-1-yl-carbonylamino,piperidin-1-yl-carbonylamino, morpholin-4-yl-carbonylamino,piperazin-1-yl-carbonylamino, 4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonylamino, cyano, carboxy, C₁₋₃-alkyloxy-carbonyl, aminocarbonyl,C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃alkyl)-aminocarbonyl,pyrrolidin-1-yl-carbonyl, 2-(methoxymethyl)-pyrrolidin-1-yl-carbonyl,3-(methoxymethyl)-pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl,morpholin-4-yl -carbonyl, piperazin-1-yl-carbonyl,4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl, N—(C₁₋₃-alkyl)-(het)arylaminocarbonyl,N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkylaminocarbonyl, C₁₋₃-alkyl-carbonyl,(het)aryl-carbonyl, hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-C₁₋₃-alkyl,amino-C₁₋₃-alkyl, C₁₋₃-alkylamino-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl, pyrrolidin-1-yl-C₁₋₃-alkyl,2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyl, morpholin-4-yl-C₁₋₃-alkyl,(methyl-morpholin-4-yl)-C₁₋₃-alkyl,(dimethyl-morpholin-4-yl)-C₁₋₃-alkyl, 3-oxo-morpholin-4-yl-C₁₋₃-alkyl,C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl, (het)arylcarbonylamino-C₁₋₃-alkyl,hydroxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-C₁₋₃-alkyloxy, trifluoromethyl,difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoro-1-hydroxyethyl,2,2,2-trifluoro-1-hydroxy-1-methylethyl,2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl, aminosulfonyl,(het)aryl, (het)aryl-C₁₋₃-alkyl, or (het)aryloxy, wherein theabove-mentioned (het)aryl groups are phenyl, naphthyl, pyrrolyl,furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl,quinolinyl, and isoquinolinyl, or pyrrolyl, furanyl, thienyl, or pyridylwherein 1 or 2 CH are replaced by N, or indolyl, benzofuranyl,benzothiophenyl, quinolinyl, or isoquinolinyl wherein 1 to 3 CH arereplaced by N, and wherein the above-mentioned (het)aryl groupsoptionally are substituted with R¹⁰ R⁵ and R⁶ are independently selectedfrom among fluorine, chlorine, bromine, C₁₋₃-alkyl, C₂₋₃-alkynyl,trifluoromethyl, hydroxy, C₁₋₃-alkyloxy, and cyano, or if R⁵ and R⁶ arebound to adjacent carbon atoms they together may additionally denotemethylenedioxy, difluoromethylenedioxy, ethylenedioxy, or C₃₋₅-alkylene,R⁷ denotes fluorine, chlorine, C₁₋₄-alkyl, hydroxy, C₁₋₄-alkyloxy,nitro, amino, C₁₋₃-alkylamino, 2-oxo-pyrrolidin-1-yl,2-oxo-piperidin-1-yl, morpholin-4-yl, 3-oxo-morpholin-4-yl,C₁₋₃-alkyl-carbonylamino, (het)aryl-carbonylamino,C₁₋₃-alkyl-sulfonylamino, N—(C₁₋₃-alkyl)-C₁ ₋₃ -alkyl-carbonylamino,N—(C₁₋₃-alkyl)-(het)arylcarbonylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-sulfonylamino,N—(C₁₋₃-alkyl)-(het)arylsulfonylamino, cyano, (hydroxyimino)aminomethyl,(C₁₋₃-alkyloxyimino)aminomethyl, carboxy, C₁₋₃-alkyloxy-carbonyl,aminocarbonyl, C₁₋₃ -alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,pyrrolidin-1-yl-carbonyl, piperidin-1-yl -carbonyl,morpholin-4-yl-carbonyl, C₁₋₃-alkyl-carbonyl, carboxy-C₁₋₃-alkyl,C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyl, cyano-C₁₋₃-alkyl,aminocarbonyl-C₁₋₃-alkyl, C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl,pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl, piperidin-1-yl-carbonyl-C₁₋₃-alkyl,morpholin-4-yl -carbonyl-C₁₋₃-alkyl, cyano-C₁₋₃-alkyloxy,aminocarbonyl-C₁₋₃-alkyloxy, C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyloxy,di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyloxy,pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl-oxy,piperidin-1-yl-carbonyl-C₁₋₃-alkyloxy,morpholin-4-yl-carbonyl-C₁₋₃-alkyl-oxy, hydroxy-C₁₋₃-alkyl,C₁₋₃-alkyloxy-C₁₋₃-alkyl, C₁₋₄-alkylcarbonyl-amino-C₁₋₃-alkyl,N—(C₁₋₃-alkyl)-C₁₋₄-alkylcarbonyl-amino-C₁₋₃-alkyl,2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyl, 2-oxo-piperid-in-1-yl-C₁₋₃-alkyl,3-oxo-morpholin-4-yl-C₁₋₃-alkyl, hydroxy-C₁₋₃-alkyloxy,C₁₋₃-alkyloxy-C₁₋₃-alkyloxy, C₁₋₄-alkylsulfanyl, C₁₋₄-alkysulfinyl,C₁₋₄-alkylsulfonyl, C₃₋₆-cycloalkylsulfanyl, C₃₋₆-cycloalkylsulfinyl,C₃₋₆-cycloalkylsulfonyl, aminosulfonyl, C₁₋₃-alkyl-aminosulfonyl,di-(C₁₋₃-alkyl)-aminosulfonyl, trifluoromethyl, difluoromethoxy,trifluoromethoxy, C₃₋₆-cycloalkyloxy, tetrahydrofuran-3-yloxy,tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy,tetrahydrofuranyl-C₁₋₃-alkyloxy, tetrahydropyranyl-C₁₋₃-alkyloxy,(het)aryl or (het)aryloxy, wherein the above-mentioned (het)aryl groupsfor R⁷ denote phenyl, furanyl, thienyl, oxazolyl, thiazolyl, isoxazolyl,imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, wherein any of thesegroups are optionally mono-or disubstituted with R¹⁰, R⁸ and R⁹, whichmay be identical or different, denote fluorine, chlorine, bromine,C₁₋₃-alkyl, trifluoromethyl, hydroxy, C₁₋₃-alkyloxy, or cyano, or if R⁸and R⁹ are bound to adjacent carbon atoms they together may additionallydenote methylenedioxy, difluoromethylenedioxy, ethylenedioxy,C₃₋₅-alkylene, R¹⁰ denotes fluorine, chlorine, methyl, difluoromethyl,trifluoromethyl, cyano, hydroxy, methoxy, difluoromethoxy, ortrifluoromethoxy, R¹¹ denotes fluorine, C₁₋₃-alkyl, hydroxyl, orC₁₋₃-alkyloxy, R¹² denotes fluorine, or C₁₋₃-alkyl, R¹³ and R¹⁴, whichmay be identical or different, denote C₁₋₃-alkyl, or a tautomer,stereoisomer, mixture thereof or salt thereof.
 4. A compound accordingto claim 1, wherein R¹ denotes, benzofuranyl, indolyl, benzothiophenyl,quinolinyl, or isoquinolinyl, wherein any of these groups optionally areindependently substituted with one R⁴ and and/or one to four differentor identical R⁵, R² and R³, together with the double bond to which theyare attached, denote a benzo or pyrido ring, optionally bothindependently substituted with R⁷, R⁸ and R⁹, R⁴ denotes fluorine,chlorine, C₁₋₄-alkyl, hydroxy, C₁₋₄-alkyloxy, amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl,C₁₋₃-alkyl-carbonylamino, aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, (N-methyl) -benzylaminocarbonyl,(N-methyl)-phenylaminocarbonyl, pyrrolidin-1-yl-carbonyl,2-(methoxymethyl)-pyrrolidin-1-yl-carbonyl,3-(methoxymethyl)-pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl,morpholin-4-yl-carbonyl, hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-C₁₋₃-alkyl,amino-C₁₋₃-alkyl, C₁₋₃-alkylamino-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl, morpholin-4-yl-C₁₋₃-alkyl,(2-methyl-morpholin-4-yl)-C₁₋₃-alkyl,(2,6-dimethyl-morpholin-4-yl)-C₁₋₃-alkyl, 3-oxo-morpholin-4-yl-methyl,pyrrolidin-1-yl-C₁₋₃-alkyl, 2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyl,C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl, phenylcarbonylamino-C₁₋₃-alkyl,imidazolyl-C₁₋₃-alkyl, triazolyl-C₁₋₃-alkyl, trifluoromethyl,difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoro-1-hydroxyethyl,2,2,2-trifluoro-1-hydroxy-1-methylethyl, or2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, or aminosulfonyl R⁵and R⁶ are independently selected from among fluorine, chlorine,bromine, C₁₋₃-alkyl, C₂₋₃-alkynyl, trifluoromethyl, hydroxy,C₁₋₃-alkyloxy, and cyano, or if R⁵ and R⁶ are bound to adjacent carbonatoms they together may additionally denote methylenedioxy,difluoromethylenedioxy, ethylenedioxy, or C₃₋₅-alkylene, R⁷ denotesfluorine, chlorine, C₁₋₃-alkyl, hydroxy, C₁₋₃-alkyloxy, amino,C₁₋₃-alkyl -carbonylamino, C₁₋₃-alkyl-sulfonylamino, cyano,(hydroxyimino)aminomethyl, carboxy, C₁₋₃-alkyloxy-carbonyl,aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,hydroxy-C₁₋₃-alkyl, trifluoromethyl-hydroxy-C₁₋₃-alkyl,C₁₋₃-alkyloxy-C₁₋₃-alkyl, C₁₋₃-alkyl -carbonyl-amino-C₁₋₃-alkyl,hydroxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-C₁₋₃-alkyloxy, trifluoromethyl,difluoromethoxy, trifluoromethoxy, C₁₋₃-alkylcarbonyl,C₁₋₄-alkylsulfonyl, C₃₋₆-cycloalkylsulfonyl, aminosulfonyl,C₁₋₃-alkyl-aminosulfonyl, or di-(C₁₋₃-alkyl)-aminosulfonyl, or a(het)aryl group selected from phenyl, pyrrol-1-yl, 4-methyl-4H-[1,2,4]triazol-3-yl, oxadiazolyl, pyridinyl,1,2-dihydro-1-methyl-2-oxo-pyridinyl, pyrimidinyl, pyridazinyl, and2,3-dihydro-2-methyl-3-oxo-pyridazinyl, each of them being optionallymono-substituted with R¹⁰; R⁸ and R⁹, which may be identical ordifferent, denote fluorine, chlorine, bromine, C₁₋₃-alkyl,trifluoromethyl, hydroxy, C₁₋₃-alkyloxy, or cyano, or if R⁸ and R⁹ arebound to adjacent carbon atoms they together may additionally denotemethylenedioxy, difluoromethylenedioxy, ethylenedioxy, C₃₋₅-alkylene,R¹⁰ denotes fluorine, chlorine, methyl, difluoromethyl, trifluoromethyl,cyano, hydroxy, methoxy, difluoromethoxy, or trifluoromethoxy, R¹¹denotes fluorine, C₁₋₃-alkyl, hydroxyl, or C₁₋₃-alkyloxy, R¹² denotesfluorine, or C₁₋₃-alkyl, R¹³ and R¹⁴, which may be identical ordifferent, denote C₁₋₃-alkyl, or a tautomer, stereoisomer, mixturethereof or salt thereof.
 5. The compound according to claim 1, whereinR¹ benzofuranyl or indolyl, wherein any of these groups optionally areindependently substituted with one R⁴ and/or one to four different oridentical R⁵ R² and R³, together with the double bond to which they areattached, denote a benzo or pyrido ring, both optionally independentlysubstituted with R⁷, R⁸ and R⁹, R⁴ denotes fluorine, chlorine, bromine,C₁₋₄-alkyl, hydroxy, C₁₋₄-alkyloxy, amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)amino, pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl,piperidin-1-yl, 2-oxo-piperidin-1-yl, morpholin-4-yl,3-oxo-morpholin-4-yl, piperazin-1-yl, 2-oxo-piperazin-1-yl,3-oxo-piperazin-1-yl, 4-(C₁₋₃-alkyl)-piperazin-1-yl, 4-(C₁₋₄-alkyl-carbonyl)-piperazin-1-yl, 4-(C₃₋₆-cycloalkylcarbonyl)-piperazin-1-yl,4-(C₁₋₄-alkyloxy -carbonyl)-piperazin-1-yl,4-(C₁₋₄-alkylsulfonyl)-piperazin-1-yl, 2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl, 3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,C₁₋₃-alkyl-carbonylamino, (het)arylcarbonylamino,(het)aryl-C₁₋₃-alkyl-carbonylamino, C₁₋₃ -alkyloxy-carbonylamino,aminocarbonylamino, C₁₋₃-alkyl-aminocarbonylamino,di-(C₁₋₃-alkyl)aminocarbonylamino, pyrrolidin-1-yl-carbonylamino,piperidin-1-yl-carbonylamino, morpholin-4-yl-carbonylamino,piperazin-1-yl-carbonylamino, 4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonylamino, cyano, carboxy, C₁₋₃-alkyloxy-carbonyl, aminocarbonyl,C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,pyrrolidin-1-yl-carbonyl, 2-(methoxymethyl)-pyrrolidin-1-yl-carbonyl,3-(methoxymethyl)-pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl,morpholin-4-yl -carbonyl, piperazin-1-yl-carbonyl,4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl, N—(C₁₋₃-alkyl)-(het)arylaminocarbonyl,N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkylaminocarbonyl, C₁₋₃-alkyl-carbonyl,(het)aryl-carbonyl, hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-C₁₋₃-alkyl,amino-C₁₋₃-alkyl, C₁₋₃-alkylamino-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl, pyrrolidin-1-yl-C₁₋₃-alkyl,2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyl, morpholin-4-yl-C₁₋₃-alkyl,(methyl-morpholin-4-yl)-C₁₋₃-alkyl, (dimethyl-morpholin-4-yl)-C₁₋₃-alkyl, 3-oxo-morpholin-4-yl-C₁₋₃-alkyl,C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl, (het)arylcarbonylamino-C₁₋₃-alkyl,hydroxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-C₁₋₃-alkyloxy, trifluoromethyl,difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoro-l-hydroxyethyl,2,2,2-trifluoro-1-hydroxy-1-methylethyl,2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl, aminosulfonyl,(het)aryl, (het)aryl-C₁₋₃-alkyl, or (het)aryloxy, wherein theabove-mentioned (het)aryl groups are phenyl, naphthyl, pyrrolyl,furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl,quinolinyl, and isoquinolinyl, or pyrrolyl, furanyl, thienyl, or pyridylwherein 1 or 2 CH are replaced by N, or indolyl, benzofuranyl,benzothiophenyl, quinolinyl, or isoquinolinyl wherein 1 to 3 CH arereplaced by N, and wherein the above-mentioned (het)aryl groupsoptionally are substituted with R¹⁰, R⁵ and R⁶ are independentlyselected from fluorine, chlorine, methyl, ethyl, ethynyl,trifluoromethyl, hydroxy, methoxy, and ethoxy, or if R⁵ and R⁶ are boundto adjacent carbon atoms they together may additionally denotemethylenedioxy, ethylene-1,2-dioxy, propylene, or butylene, R⁷ denotesfluorine, chlorine, C₁₋₄-alkyl, hydroxy, C₁₋₄-alkyloxy, nitro, amino,C₁₋₃-alkylamino, 2-oxo-pyrrolidin-1-yl, 2-oxo-piperidin-1-yl,morpholin-4-yl, 3-oxo-morpholin-4-yl, C₁₋₃-alkyl-carbonylamino,(het)aryl-carbonylamino, C₁₋₃-alkyl-sulfonylamino, N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-carbonylamino, N—(C₁₋₃-alkyl)-(het)arylcarbonylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-sulfonylamino,N—(C₁₋₃-alkyl)-(het)arylsulfonylamino, cyano, (hydroxyimino)aminomethyl,(C₁₋₃-alkyloxyimino)aminomethyl, carboxy, C₁₋₃-alkyloxy-carbonyl,aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,pyrrolidin-1-yl-carbonyl, piperidin-1-yl -carbonyl,morpholin-4-yl-carbonyl, C₁₋₃-alkyl-carbonyl, carboxy-C₁₋₃-alkyl,C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyl, cyano-C₁₋₃-alkyl,aminocarbonyl-C₁₋₃-alkyl, C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl,pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl, piperidin-1-yl-carbonyl-C₁₋₃-alkyl,morpholin-4-yl -carbonyl-C₁₋₃-alkyl, cyano-C₁₋₃-alkyloxy,aminocarbonyl-C₁₋₃-alkyloxy, C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyloxy,di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyloxy,pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl-oxy,piperidin-1-yl-carbonyl-C₁₋₃-alkyloxy,morpholin-4-yl-carbonyl-C₁₋₃-alkyl-oxy, hydroxy-C₁₋₃-alkyl, C₁ ₋₃-alkyloxy-C₁₋₃-alkyl, C₁₋₄-alkylcarbonyl-amino-C₁₋₃-alkyl,N—(C₁₋₃-alkyl) -C₁₋₄-alkylcarbonyl-amino-C₁₋₃-alkyl,2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyl, 2-oxo-piperid-in-1-yl-C₁₋₃-alkyl,3-oxo-morpholin-4-yl-C₁₋₃-alkyl, hydroxy-C₁₋₃-alkyloxy,C₁₋₃-alkyloxy-C₁₋₃-alkyloxy, C₁₋₄-alkylsulfanyl, C₁₋₄-alkysulfinyl,C₁₋₄-alkylsulfonyl, C₃₋₆-cycloalkylsulfanyl, C₃₋₆-cycloalkylsulfinyl,C₃₋₆-cycloalkylsulfonyl, aminosulfonyl, C₁₋₃-alkyl-aminosulfonyl,di-(C₁₋₃-alkyl)-aminosulfonyl, trifluoromethyl, difluoromethoxy,trifluoromethoxy, C₃₋₆-cycloalkyloxy, tetrahydrofuran-3-yloxy,tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy,tetrahydrofuranyl-C₁₋₃-alkyloxy, tetrahydropyranyl-C₁₋₃-alkyloxy,(het)aryl or (het)aryloxy, wherein the above-mentioned (het)aryl groupsfor R⁷ denote phenyl, furanyl, thienyl, oxazolyl, thiazolyl, isoxazolyl,imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, wherein any of thesegroups are optionally mono- or disubstituted with R¹⁰, R⁸ and R⁹independently denote fluorine, chlorine, methyl, ethyl, isopropyl,trifluoromethyl, hydroxy, methoxy, ethoxy, or cyano, or if R⁸ and R⁹ arebound to adjacent carbon atoms they together may additionally denotemethylenedioxy, ethylene-1,2-dioxy, propylene, butylene or R¹⁰ denotesfluorine, chlorine, methyl, difluoromethyl, trifluoromethyl, cyano,hydroxy, methoxy, difluoromethoxy, or trifluoromethoxy, R¹¹ denotesfluorine, C₁₋₃-alkyl, hydroxyl, or C₁₋₃-alkyloxy, R¹² denotes fluorine,or C₁₋₃-alkyl, R¹³ and R¹⁴, which may be identical or different, denoteC₁₋₃-alkyl, or a tautomer, stereoisomer, mixture thereof or saltthereof.
 6. A physiologically acceptable salt of the compound accordingto claim 1 with an inorganic or organic acid or base.
 7. Apharmaceutical composition containing a compound according to claim 1,or a physiologically acceptable salt with an inorganic or organic acidor base, optionally together with one or more inert carriers and/ordiluents.
 8. A method of inhibiting, 11β-hydroxysteroid dehydrogenase(HSD) 1 comprising administering to a patient in need thereof a compoundof formula I

wherein R¹ denotes heteroaryl selected from the group consisting ofindolyl, benzofuranyl, benzothiophenyl, quinolinyl, and isoquinolinyl,wherein 1 to 3 CH of said heteroaryls are optionally replaced by N,wherein the above-mentioned heteroaryl rings are optionally substitutedwith one R⁴, one to four identical or different R⁵, and/or one R⁶, andall heteroaryl rings are attached to the carbonyl group via a carbonatom, R² and R³ together with the double bond to which they are attacheddenote a benzo ring optionally substituted with R⁷, R⁸ and R⁹, or apyrido ring optionally substituted with R⁷, R⁸ and R⁹, R⁴ denotesfluorine, chlorine, bromine, iodine, C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, hydroxy, C₁₋₄-alkyloxy, nitro, amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)amino, pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl,piperidin-1-yl, 2-oxo-piperidin-1-yl, morpholin-4-yl,3-oxo-morpholin-4-yl, piperazin-1-yl, 2-oxo-piperazin-1-yl,3-oxo-piperazin-1-yl, 4-(C₁₋₃-alkyl)-piperazin-1-yl,4-(C₁₋₄-alkylcarbonyl)-piperazin-1-yl,4-(C₃₋₆-cycloalkylcarbonyl)-piperazin-1-yl,4-(C₁₋₄-alkyloxycarbonyl)-piperazin-1-yl,4-(C₁₋₄-alkylsulfonyl)-piperazin-1-yl,2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl,3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl, C₁₋₃-alkyl-carbonylamino,(het)aryl-carbonylamino, (het)aryl-C₁₋₃-alkyl-carbonylamino,C₁₋₃-alkyloxy-carbonylamino, aminocarbonylamino,C₁₋₃-alkyl-aminocarbonylamino, di-(C₁₋₃-alkyl)aminocarbonylamino,pyrrolidin-1-yl-carbonylamino, piperidin-1-yl -carbonylamino,morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino,4-(C₁₋₃-alkyl) -piperazin-1-yl-carbonylamino, C₁₋₃-alkyl-sulfonylamino,aminosulfonylamino, C₁₋₃-alkylamino-sulfonylamino,di-(C₁₋₃-alkyl)amino-sulfonylamino, pyrrolidin-1-yl-sulfonylamino,piperidin-1-yl-sulfonylamino, morpholin-4-yl-sulfonylamino, piperazin-1-yl-sulfonylamino, 4-(C₁₋₃-alkyl)-piperazin-1-yl-sulfonylamino,(C₁₋₃-alkyloxy -carbonylamino)carbonylamino, (het)arylsulfonylamino,(het)aryl-C₁₋₃-alkyl- sulfonylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-carbonylamino,N—(C₁₋₃-alkyl)-(het)arylcarbonylamino, N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkyl-carbonylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkyloxy-carbonyl-amino,N-(aminocarbonyl)-C₁₋₃-alkylamino,N—(C₁₋₃-alkyl-aminocarbonyl)-C₁₋₃-alkylamino,N-[di-(C₁₋₃-alkyl)aminocarbonyl]-C₁₋₃-alkylamino,N—(C₁₋₃-alkyl)-C₁₋₃-alkyl-sulfonylamino,N—(C₁₋₃-alkyl)-(het)arylsulfonylamino,N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkyl-sulfonylamino,oxo-imidazolidin-1-yl, 2,4-dioxo-imidazolidin-1-yl,2,5-dioxo-imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl, wherein thenitrogen atom in position 3 of the aforementioned groups is optionallysubstituted with methyl or ethyl, cyano, carboxy,C₁₋₃-alkyloxy-carbonyl, aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl, pyrrolidin-1-yl-carbonyl,piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl,piperazin-1-yl-carbonyl, 4-(C₁₋₃-alkyl)-piperazin-1-yl -carbonyl,(het)arylaminocarbonyl, N—(C₁₋₃-alkyl)-(het)arylaminocarbonyl,(het)aryl-C₁₋₃-alkylaminocarbonyl,N—(C₁₋₃-alkyl)-(het)aryl-C₁₋₃-alkylaminocarbonyl, C₁₋₃-alkyl-carbonyl,(het)aryl-carbonyl, carboxy-C₁₋₃-alkyl,C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyl, cyano-C₁₋₃-alkyl, ami-nocarbonyl-C₁₋₃-alkyl, C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl,pyrrolidin-1-yl-carbonyl-C₁₋₃-alkyl, piperidin-1-yl-carbonyl-C₁₋₃-alkyl,morpholin-4-yl-carbonyl-C₁₋₃-alkyl, piperazin-1-yl-carbonyl-C₁₋₃-alkyl,4-(C₁₋₃-alkyl) -piperazin-1-yl-carbonyl-C₁₋₃-alkyl,carboxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkyloxy,cyano-C₁₋₃-alkyloxy, aminocarbonyl-C₁₋₃-alkyloxy,C₁₋₃-alkyl-aminocarbonyl-C₁₋₃-alkyloxy, di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyloxy, pyrrolidin-1 -yl-carbonyl-C₁₋₃-alkyl-oxy,piperidin-1-yl -carbonyl-C₁₋₃-alkyloxy,morpholin-4-yl-carbonyl-C₁₋₃-alkyl-oxy, piperazin-1-yl-carbonyl-C₁₋₃-alkyloxy,4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl-C₁₋₃-alkyloxy,hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyloxy-C₁₋₃-alkyl, amino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,pyrrolidin-1-yl-C₁₋₃-alkyl, 2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyl,piperidin-1-yl-C₁₋₃-alkyl, 2-oxo-piperidin-1-yl-C₁₋₃-alkyl,morpholin-4-yl -C₁₋₃-alkyl, 3-oxo-morpholin-4-yl-C₁₋₃-alkyl,piperazin-1-yl-C₁₋₃-alkyl, 2-oxo-piperazin-1-yl-C₁₋₃-alkyl,3-oxo-piperazin-1-yl-C₁₋₃-alkyl,4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyl,2-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyl,3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyl,C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl, arylcarbonylamino-C₁₋₃-alkyl,hydroxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxy-C₁₋₃-alkyloxy,C₁₋₃-alkylsulfanyl-C₁₋₃-alkyloxy, C₁₋₃-alkylsulfinyl-C₁₋₃-alkyloxy,C₁₋₃-alkylsulfonyl-C₁₋₃-alkyloxy, amino-C₁₋₃-alkyloxy,C₁₋₃-alkylamino-C₁₋₃-alkyloxy, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyloxy,pyrrolidin-1-yl-C₁₋₃-alkyloxy, 2-oxo-pyrrolidin-1-yl-C₁₋₃-alkyloxy,piperidin-1-yl-C₁₋₃-alkyloxy, 2-oxo -piperidin-1-yl-C₁₋₃-alkyloxy,morpholin-4-yl-C₁₋₃-alkyloxy, 3-oxo-morpholin-4-yl-C₁₋₃-alkyloxy,piperazin-1-yl-C₁₋₃-alkyloxy, 2-oxo-piperazin-1-yl-C₁₋₃-alkyloxy, 3-oxo-piperazin-1-yl-C₁₋₃-alkyloxy,4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyloxy, 2-oxo-4-(C₁₋₃-alkyl)-piperazin-1 -yl-C₁₋₃-alkyloxy,3-oxo-4-(C₁₋₃-alkyl)-piperazin-1-yl-C₁₋₃-alkyloxy, C₁₋₃-alkylsulfanyl,C₁₋₃-alkysulfinyl, C₁₋₃-alkylsulfonyl, C₁₋₃-alkylsulfonyloxy,(het)arylsulfonyl, (het)arylsulfonyloxy, trifluoromethylsulfanyl,trifluoromethylsulfinyl, trifluoromethylsulfonyl, aminosulfonyl,C₁₋₃-alkyl-aminosulfonyl, di-(C₁₋₃-alkyl)-aminosulfonyl,pyrrolidin-1-yl-sulfonyl, piperidin-1-yl-sulfonyl,morpholin-4-yl-sulfonyl, piperazin-1-yl-sulfonyl,4-(C₁₋₃-alkyl)-piperazin-1-yl-sulfonyl, difluoromethyl, trifluoromethyl,difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoro-1-hydroxyethyl,2,2,2-trifluoro-1-hydroxy-1-methylethyl,2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyloxy, C₃₋₆-cycloalkyl-C₁₋₃-alkyl,C₃₋₆-cycloalkyl-C₁₋₃-alkyloxy, (het)aryl, (het)aryloxy,(het)aryl-C₁₋₃-alkyl, (het)aryl-C₁₋₃-alkyloxy, (het)aryloxy-C₁₋₃-alkyl,or tetrahydrofuran-3-yl-oxy, tetrahydropyran-3-yl-oxy,tetrahydropyran-4-yl-oxy, tetrahydrofuranyl-C₁₋₃-alkyloxy,tetrahydropyranyl-C₁₋₃-alkyloxy, wherein the above-mentionedpyrrolidin-1-yl and piperidin-1-yl moieties are optionally substitutedwith one or two groups selected from methyl, ethyl, methoxymethyl,hydroxy or methoxy, and, wherein the above-mentioned piperazin-1-yl andmorpholin-4-yl moieties are optionally substituted with one or twogroups selected from methyl, ethyl or methoxymethyl, and wherein theabove-mentioned (het)aryl is phenyl, naphthyl, pyrrolyl, furanyl,thienyl, tetrazolyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl,quinolinyl, isoquinolinyl, or pyrrolyl, furanyl, thienyl, pyridyl inwhich 1 or 2 CH are replaced by N, or indolyl, benzofuranyl,benzothiophenyl, quinolinyl, isoquinolinyl in which 1 to 3 CH arereplaced by N, or 1,2-dihydro-2-oxo-pyridinyl,1,4-dihydro-4-oxo-pyridinyl, 2,3-dihydro-3-oxo -pyridazinyl,1,2,3,6-tetrahydro-3,6-dioxo-pyridazinyl, 1,2-dihydro-2-oxo-pyrimidinyl,3,4-dihydro-4-oxo-pyrimidinyl, 1,2,3,4-tetrahydro-2,4-dioxo-pyrimidinyl,1,2-dihydro -2-oxo-pyrazinyl, 1,2,3,4-tetrahydro-2,3-dioxo-pyrazinyl,2,3-dihydro-2-oxo-indolyl, 2,3-dihydrobenzofuranyl,2,3-dihydro-2-oxo-1H-benzimidazolyl, 2,3-dihydro-2-oxo -benzoxazolyl,1,2-dihydro-2-oxo-quinolinyl, 1,4-dihydro-4-oxo-quinolinyl,1,2-dihydro-1-oxo-isoquinolinyl, 1,4-dihydro-4-oxo-cinnolinyl,1,2-dihydro-2-oxo -quinazolinyl, 1,4-dihydro-4-oxo-quinazolinyl,1,2,3,4-tetrahydro-2,4-dioxo -quinazolinyl,1,2-dihydro-2-oxoquinoxalinyl, 1,2,3,4-tetrahydro-3-oxo-quinoxalinyl,1,2,3,4-tetrahydro-2,3-dioxo-quinoxalinyl,1,2-dihydro-1-oxo-phthalazinyl,1,2,3,4-tetrahydro-1,4-dioxo-phthalazinyl, chromanyl, coumarinyl,2,3-dihydro -benzo[1,4]dioxinyl,3,4-dihydro-3-oxo-2H-benzo[1,4]oxazinyl, and wherein the above-mentioned(het)aryl groups are optionally substituted with one or two R¹⁰ whichmay be identical or different, R⁵ and R⁶, which may be identical ordifferent, denote halogen, C₁₋₃-alkyl, C₂₋₃-alkynyl, trifluormethyl,hydroxy, C₁₋₃-alkyloxy, cyano, or R⁵ together with R⁶, if bound toadjacent carbon atoms, may additionally be methylenedioxy,difluoromethylenedioxy, ethylenedioxy, C₃₋₅-alkylene, or R⁷ denotesfluorine, chlorine, bromine, iodine, C₁₋₄-alkyl, hydroxy, C₁₋₄-alkyloxy,nitro, amino, C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)amino, pyrrolidin-1-yl,2-oxo-pyrrolidin-1-yl, piperidin-1-yl, 2-oxo-piperidin-1-yl,morpholin-4-yl, 3-oxo-morpholin-4-yl, piperazin-1-yl,2-oxo-piperazin-1-yl, 3-oxo-piperazin-1-yl,4-(C₁₋₄-alkyl)-pi-perazin-1-yl, 4-(C₁₋₄-alkylcarbonyl)-piperazin-1-yl,4-(C₃₋₆-cycloalkylcarbonyl)-piperazin-1-yl,4-(C₁₋₄-alkyloxycarbonyl)-piperazin-1-yl,4-(C₁₋₄-alkylsulfonyl)-piperazin-1-yl,2-oxo-4-(C₁₋₄-alkyl)-piperazin-1-yl,3-oxo-4-(C₁₋₄-alkyl)-piperazin-1-yl, C₁₋₄-alkyl-carbonylamino,(het)aryl-carbonylamino, (het)aryl-C₁₋₄-alkyl-carbonylamino,C₁₋-alkyloxy-carbonylamino, aminocarbonylamino,C₁₋₄-alkyl-aminocarbonylamino, di -(C₁₋₄-alkyl)aminocarbonylamino,pyrrolidin-1-yl-carbonylamino, piperidin-1-yl-carbo-nylamino,morpholin-4-yl-carbonylamino, piperazin-1-yl-carbonylamino,4-(C₁₋₄-alkyl) -piperazin-1-yl-carbonylamino, C₁₋₄-alkyl-sulfonylamino,aminosulfonylamino, C₁₋₄-alkylamino-sulfonylamino,di-(C₁₋₄-alkyl)amino-sulfonylamino, pyrrolidin-1-yl-sulfonylamino,piperidin-1-yl-sulfonylamino, morpholin-4-yl-sulfonylamino, piperazin-1-yl-sulfonylamino, 4-(C₁₋₄-alkyl)-piperazin-1-yl-sulfonylamino,(C₁₋₄-alkyloxy -carbonylamino)carbonylamino, (het)arylsulfonylamino,(het)aryl-C₁₋₄-alkyl -sulfonylamino,N—(C₁₋₄-alkyl)-C₁₋₄-alkyl-carbonylamino,N—(C₁₋₄-alkyl)-(het)arylcarbonylamino,N—(C₁₋₄-alkyl)-(het)aryl-C₁₋₄-alkyl-carbonylamino,N—(C₁₋₄-alkyl)-C₁₋₄-alkyloxy-carbonyl -amino,N-(aminocarbonyl)-C₁₋₄-alkylamino,N—(C₁₋₄-alkyl-aminocarbonyl)-C₁₋₄-alkylamino,N-[di-(C₁₋₄-alkyl)aminocarbonyl]-C₁₋₄-alkylamino,N—(C₁₋₄-alkyl)-C₁₋₄-alkyl-sulfonylamino,N—(C₁₋₄-alkyl)-(het)arylsulfonylamino,N—(C₁₋₄-alkyl)-(het)aryl-C₁₋₄-alkyl-sulfonylamino,oxo-imidazolidin-1-yl, 2,4-dioxo-imidazolidin-1-yl,2,5-dioxo-imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl, wherein thenitrogen atom in position 3 of the aforementioned groups is optionallysubstituted with methyl or ethyl, cyano, (hydroxyimino)aminomethyl,(C₁₋₄-alkyloxyimino)aminomethyl, carboxy, C₁₋₄-alkyloxy-carbonyl,aminocarbonyl, C₁₋₄-alkyl-aminocarbonyl, di-(C₁₋₄-alkyl)-amino-carbonyl, pyrrolidin-1-yl-carbonyl, piperidin-1-yl-carbonyl,morpholin-4-yl-carbonyl, piperazin-1-yl-carbonyl,4-(C₁₋₄-alkyl)-piperazin-1-yl-carbonyl, C₁₋₄-alkyl-carbonyl,(het)aryl-carbonyl, carboxy-C₁₋₄-alkyl,C₁₋₄-alkyloxy-carbonyl-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl, aminocarbonyl-C₁₋₄-alkyl, C₁₋₄-alkyl-aminocarbonyl-C₁₋₄-alkyl,di-(C₁₋₄-alkyl)-aminocarbonyl-C₁₋₄-alkyl,pyrrolidin-1-yl-carbonyl-C₁₋₄-alkyl, piperidin-1-yl-carbonyl-C₁₋₄-alkyl,morpholin-4-yl-carbonyl-C₁₋₄-alkyl, piperazin-1-yl-carbonyl-C₁₋₄-alkyl,4-(C₁₋₄-alkyl) -piperazin-1-yl-carbonyl-C₁₋₄-alkyl,carboxy-C₁₋₄-alkyloxy, C₁₋₄-alkyloxy-carbonyl-C₁₋₄-alkyloxy,cyano-C₁₋₄-alkyloxy, amino-carbonyl-C₁₋₄-alkyloxy,C₁₋₄-alkyl-aminocarbonyl-C₁₋₄-alkyloxy, di-(C₁₋₄-alkyl)-amino-carbonyl-C₁₋₄-alkyloxy, pyrrolidin-1 -yl-carbonyl-C₁₋₄-alkyl-oxy,piperidin-1-yl -carbonyl-C₁₋₄-alkyloxy,morpholin-4-yl-carbonyl-C₁₋₄-alkyl-oxy, piperazin-1-yl-carbonyl-C₁₋₄-alkyloxy, 4-(C₁₋₄-alkyl)-piperazin-1-yl-carbonyl-C₁₋₄-alkyloxy, hydroxy-C₁₋₄-alkyl,C₁₋₄-alkyloxy-C₁₋₄-alkyl, amino-C₁₋₄-alkyl, C₁₋₄-alkylamino-C₁₋₄-alkyl,di-(C₁₋₄-alkyl)-amino-C₁₋₄-alkyl, pyrrolidin-1-yl-C₁₋₄-alkyl,C₁₋₄-alkylcarbonyl -amino-C₁₋₄-alkyl,N—(C₁₋₄-alkyl)-C₁₋₄-alkylcarbonyl-amino-C₁₋₄-alkyl, 2-oxo-pyrrolidin-1-yl-C₁₋₄-alkyl, piperidin-1 -yl-C₁₋₄-alkyl,2-oxo-piperidin-1-yl-C₁₋₄-alkyl, morpholin-4-yl-C₁₋₄-alkyl,3-oxo-morpholin-4-yl-C₁₋₄-alkyl, piperazin-1-yl-C₁₋₄-alkyl,2-oxo-piperazin-1-yl-C₁₋₄-alkyl, 3-oxo-piperazin-1-yl-C₁₋₄-alkyl,4-(C₁₋₄-alkyl) -piperazin-1-yl-C₁₋₄-alkyl,2-oxo-4-(C₁₋₄-alkyl)-piperazin-1-yl-C₁₋₄-alkyl,3-oxo-4-(C₁₋₄-alkyl)-piperazin-1-yl-C₁₋₄-alkyl, hydroxy-C₁₋₄-alkyloxy,C₁₋₄-alkyloxy-C₁₋₄-alkyloxy, C₁₋₄-alkylsulfanyl-C₁₋₄-alkyloxy,C₁₋₄-alkylsulfinyl-C₁₋₄-alkyloxy, C₁₋₄-alkylsulfonyl-C₁₋₄-alkyloxy,amino-C₁₋₄-alkyloxy, C₁₋₄-alkylamino-C₁₋₄-alkyloxy,di-(C₁₋₄-alkyl)-amino-C₁₋₄-alkyloxy, pyrrolidin-1-yl-C₁₋₄-alkyloxy,2-oxo-pyrrolidin-1-yl-C₁₋₄-alkyloxy, piperidin-1-yl-C₁₋₄-alkyloxy, 2-oxo-piperidin-1-yl-C₁₋₄-alkyloxy, morpholin-4-yl-C₁₋₄-alkyloxy, 3-oxo-morpholin-4-yl-C₁₋₄-alkyloxy, piperazin-1-yl-C₁₋₄-alkyloxy,2-oxo-piperazin-1-yl-C₁₋₄-alkyloxy, 3-oxo -piperazin-1-yl-C₁₋₄-alkyloxy,4-(C₁₋₄-alkyl)-piperazin-1-yl-C₁₋₄-alkyloxy,2-oxo-4-(C₁₋₄-alkyl)-piperazin-1 -yl-C₁₋₄-alkyloxy, 3-oxo-4-(C₁₋₄-alkyl)-piperazin-1 -yl-C₁₋₄-alkyloxy, C₁₋₄-alkylsulfanyl,C₁₋₄-alkysulfinyl, C₁₋₄-alkylsulfonyl, C₁₋₄-alkylsulfonyloxy,(het)arylsulfonyl, (het)arylsulfonyloxy, trifluoromethylsulfanyl,trifluoromethylsulfinyl, trifluoromethylsulfonyl,C₃₋₆-cycloalkylsulfanyl, C₃₋₆-cycloalkylsulfinyl,C₃₋₆-cycloalkylsulfonyl C₃₋₆-cycloalkyl-C₁₋₃-alkylsulfanyl,C₃₋₆-cycloalkyl-C₁₋₃-alkylsulfinyl, C₃₋₆-cycloalkyl-C₁₋₃-alkylsulfonyl,aminosulfonyl, C₁₋₄-alkyl-aminosulfonyl, di-(C₁₋₄-alkyl)-aminosulfonyl,pyrrolidin-1-yl-sulfonyl, piperidin-1-yl-sulfonyl,morpholin-4-yl-sulfonyl, piperazin-1-yl-sulfonyl,4-(C₁₋₄-alkyl)-piperazin-1-yl-sulfonyl, difluoromethyl, trifluoromethyl,difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoro-1-hydroxyethyl,2,2,2-trifluoro-1-hydroxy-1-methylethyl,2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyloxy, hydroxy-C₄₋₆-cycloalkyl,C₁₋₃-alkyloxy-C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyl,C₃₋₆-cycloalkyl-C₁₋₃-alkyloxy, (het)aryl, (het)aryloxy,(het)aryl-C₁₋₃-alkyl, (het)aryl-C₁₋₃-alkyloxy, (het)aryloxy-C₁₋₃-alkyl,or tetrahydrofuran-3-yl-oxy, tetrahydropyran-3-yl-oxy,tetrahydropyran-4-yl-oxy, tetrahydrofuranyl-C₁₋₃-alkyloxy,tetrahydropyranyl-C₁₋₃-alkyloxy, wherein the above-mentioned (het)arylis defined as described for R⁴ hereinbefore, R⁸ and R⁹, which may beidentical or different, are halogen, C₁₋₃-alkyl, trifluormethyl,hydroxy, C₁₋₃-alkyloxy, cyano, or R⁸ together with R⁹, if bound toadjacent carbon atoms, may additionally be methylenedioxy,difluoromethylenedioxy, ethylenedioxy, C₃₋₅-alkylene, or R¹⁰ is R^(10′)or R^(10″) and R^(10′) denotes halogen, C₁₋₃-alkyl, difluoromethyl,trifluoromethyl, cyano, nitro, amino, acetylamino, methylsulfonylamino,carboxy, C₁₋₄-alkyloxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, aminosulfonyl, methylsulfanyl,methylsulfinyl, methylsulfonyl, hydroxy, C₁₋₃-alkyloxy, difluoromethoxy,or trifluoromethoxy, R^(10′) denotes pyrrolyl, furanyl, thienyl,pyridyl, wherein in any of these groups 1 or 2 CH optionally arereplaced by N atoms, or indolyl, benzofuranyl, benzothiophenyl,quinolinyl, isoquinolinyl, wherein in any of these groups 1 to 3 CHoptionally are replaced by N atoms, or phenyl, naphthyl, tetrazolyl,1,2-dihydro-2-oxo-pyridinyl, 1,4-dihydro-4-oxo-pyridinyl,2,3-dihydro-3-oxo-pyridazinyl, 1,2,3,6-tetrahydro-3,6-dioxo-pyridazinyl,1,2-dihydro-2-oxo-pyrimidinyl, 3,4-dihydro-4-oxo-pyrimidinyl,1,2,3,4-tetrahydro-2,4-dioxo-pyrimidinyl, 1,2-dihydro-2-oxo-pyrazinyl,1,2,3,4-tetrahydro-2,3-dioxo-pyrazinyl, 2,3-dihydro-2-oxo-indolyl,2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxo-1H-benzimidazolyl,2,3-dihydro-2-oxo-benzoxazolyl, 1,2-dihydro-2-oxo-quinolinyl,1,4-dihydro-4-oxo-quinolinyl, 1,2-dihydro-1-oxo-isoquinolinyl,1,4-dihydro-4-oxo-cinnolinyl, 1,2-dihydro-2-oxo-quinazolinyl,1,4-dihydro-4-oxo-quinazolinyl,1,2,3,4-tetrahydro-2,4-dioxo-quinazolinyl,1,2-dihydro-2-oxoquinoxalinyl, 1,2,3,4-tetrahydro-3-oxo-quinoxalinyl,1,2,3,4-tetrahydro-2,3-dioxo-qui-noxalinyl,1,2-dihydro-1-oxo-phthalazinyl,1,2,3,4-tetrahydro-1,4-dioxo-phthalazinyl, chromanyl, coumarinyl,2,3-dihydro-benzo[1,4]dioxinyl, or 3,4-dihydro-3-oxo-2H-benzo[1,4]oxazinyl, and wherein any of the groups mentionedhereinbefore under R^(10″) optionally are substituted independently withone or two groups selected from halogen, C₁₋₃-alkyl, difluoromethyl,trifluoromethyl, cyano, nitro, amino, acetylamino, methylsulfonylamino,carboxy, C₁₋₄-alkyl -oxycarbonyl, aminocarbonyl,C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl, aminosulfonyl,methylsulfanyl, methylsulfinyl, methylsulfonyl, hydroxy, C₁₋₃-alkyloxy,difluoromethoxy, and trifluoromethoxy, X denotes CH, m, n, o are each 1,and wherein the bicyclic core structure of formula I is optionallysubstituted independently with R¹¹ to R¹⁴, wherein R¹¹ denotes fluorine,C₁₋₄-alkyl, (het)aryl, hydroxy, C₁₋₄-alkyloxy, cyano, carboxy,C₁₋₄-alkyloxycarbonyl, aminocarbonyl, C₁₋₄-alkylamino-carbonyl,di-(C₁₋₄-alkyl) -aminocarbonyl, hydroxy-C₁₋₄-alkyl orC₁₋₃-alkyloxy-C₁₋₄-alkyl, wherein (het)aryl is as described for R⁴hereinbefore, R¹² denotes fluorine or C₁₋₄-alkyl, and R¹³ and R¹⁴, whichmay be identical or different, denote C₁₋₄-alkyl, and wherein theabove-mentioned alkyl or alkylene moieties are branched or unbranched,or a physiologically acceptable salt with an inorganic or organic acidor base or a salt thereof wherein the patient is suffering from ametabolic disorder selected from the group consisting of type 1 and type2 diabetes mellitus, retinopathy, nephropathy or neuropathies, diabeticfoot, ulcers, macroangiopathies, slow or poor wound healing, metabolicacidosis or ketosis, reactive hypoglycaemia, hyperinsulinaemia, glucosemetabolic disorder, insulin resistance, metabolic syndrome,dyslipidaemias of different origins, atherosclerosis obesity, high bloodpressure, chronic heart failure, edema and hyperuricaemia.
 9. A processfor preparing a pharmaceutical composition, comprising incorporating acompound according to claim 1 or a physiologically acceptable salt withan inorganic or organic acid or base in one or more inert carriersand/or diluents by a non-chemical method.